The American Cancer Society recently estimated that approximately 207,090 new cases of invasive breast cancer and 54,010 new cases of carcinoma in situ (CIS) would be diagnosed in 2010, with 0.94% of those cases occurring in men.[1, 2] From these numbers, it was calculated that a woman’s lifetime risk of developing invasive breast cancer is approximately 1 in 8 (12%). Breast cancer is not only prevalent in women, but it can also be deadly—breast cancer was estimated to account for 15% of all cancer deaths in women in 2010, second only to lung cancer (26%). Overall, these statistics emphasize the need to develop meaningful methods of breast cancer prevention and treatment to decrease the devastating impact of the disease.
In past years oncologists had generally given the recommendation to their breast cancer patients to “take it easy” during treatment. This was due to the fact that the effect of exercise during active cancer treatment had not been extensively studied, and most physicians chose to take a conservative approach. Exercise in terms of risk reduction and prevention of recurrence was also poorly understood. As the body of research grew in recent years, exercise was found to have value in these areas and basic recommendations emerged. The specifics of these recommendations as set forth by the American College of Sports Medicine (ACSM) and American Cancer Society (ACS) are contained in the tables below. The aim of this page is to not only examine the basis of these recommendations, but to delve beyond them by examining the effects of exercise on breast cancer patients at the cellular level. The purpose of this is to attempt to discern how activity can specifically impact these disease processes and evaluate where future trends for breast cancer and exercise are headed.
|Parameter||Exercise Prescription Recommendations from ACSM Guidelines|
|Frequency||Aerobic exercise 3 to 5 days a week; resistance exercise 2 to 3 days a week; allowing for at least a 48 hour recovery between sessions; and flexibility exercises 2 to 7 times a week|
|Intensity||Aerobic exercise: 40 to 60% oxygen uptake reserve or heart rate reserve; Resistance exercise: 40 to 60% of 1-RM; and flexibility exercise: slow static stretching to the point of tension|
|Time||Aerobic exercise: 20-60 minutes a day with accumulated shorter bouts if necessary due to fatigue/time constraints; Resistance exercise: 1 to 3 sets of 8 to 12 reps per exercise, with an upper limit of 15 reps appropriate for deconditioned, fatigued, or frail individuals; Flexibility exercises: 4 reps of 10 to 30 seconds per stretch|
|Type||Aerobic exercise: prolonged, rhythmic activities using large muscle groups like walking, cycling, and swimming; Resistance exercises: weights, resistance machines, or weight-bearing functional tasks like sit to stands; Flexibility exercise: stretching or ROM exercise of all major muscle groups also addressing specific areas that may be restricted due to treatment or surgery|
|Parameter||Exercise Prescription Recommendations for Breast Cancer Patients Currently Receiving Treatment|
|Frequency||At least 3 to 5 times a week, however daily exercise may be preferred for those who are deconditioned and require lower intensities and short durations of exercise|
|Intensity||Moderate intensity depending on the current level of fitness and their specific side effects to current treatments. Guidelines include 50 to 75% of their VO2max, 60 to 80% of their max heart rate, or RPE of 11 to 14.|
|Time||At least 20 to 30 minutes of continuous activity, however this may include several short bouts adding up to the goal time due to deconditioning of patient or if the patient is experiencing side effects of their treatments|
|Type||Exercises that include multiple muscle groups like walking or cycling are the best. The key is to modify the mode depending on if they are in acute or chronic phases of surgery, chemotherapy, or radiation therapy.|
Table of Contents
2. Exercise and Reduction of Breast Cancer Risk
In 2007, a systematic review summarized the body of literature linking exercise with breast cancer risk. Together, the reviewed studies showed that moderate exercise may decrease a woman’s risk of developing breast cancer by 20 to 80%, with a consistent inverse relationship between the amount of physical activity and breast cancer risk.[7, 8, 9] Overall, the evidence for exercise in prevention of breast cancer is stronger for postmenopausal women than premenopausal women. If the regimen is maintained over time, statistical analysis showed a 6% decrease in breast cancer risk for each additional hour of moderate exercise per week. It should be noted that, although this review demonstrates positive effects of physical activity on breast cancer risk, the review only examined whether or not participants developed breast cancer and not the cellular mechanisms which may have contributed. Theories on why exercise demonstrates preventative effects on breast cancer development and specific exercise prescriptions are discussed in the sections below.
a. DNA Methylation, Exercise, and Risk Reduction
Aberrant changes in the methylation status of cytosine in the CpG islands of nucleotides will lead to upregulation of proto-oncogenes and downregulation of tumor-suppressor genes. This methylation process is a primary part of a larger focus, called epigenetics, which also includes histone modification and microRNA activity. Unlike genetic mutations, which are hereditary and irreversible, epigenetic alterations are fundamentally reversible, and therefore are becoming an increasingly relevant focus of the treatment and prevention of carcinogenesis research. It has been determined that DNA methylation is related with dietary and lifestyle factors, with low folate and high alcohol intake associated with colorectal cancer, cigarette smoking with lung cancer, and high salt intake in gastric cancer, and with the increased intake of fruits and vegetables potentially decreasing methylation. DNA methylation has also been hypothesized to be related to physical activity[10, 11, 12], with one study suggesting that DNA methylation is related to circulating estrogen levels. It is important to consider dietary changes in conjunction with physical activity as they are interrelated in molecular mechanisms, and poor performance of these two variables can often result in several cancer risk factors. The purpose of this discussion, however, will be to focus on the effects of physical activity on methylation alterations and breast cancer risk reduction.
i. Evidence of DNA Methylation Prevention
While the exact relationship has yet to be determined, evidence exists that establishes a link between exercise and alterations in the methylation status of certain genes in healthy individuals, representing a potential application for cancer risk reduction. A randomized controlled trial conducted by Nakajima et al. with healthy elderly and young adults, utilized a high-intensity, aerobic interval walking program (3-minute intervals of 40 and 70% of peak aerobic capacity for a minimum of 26 minutes per day, and minimum of 2 days per week) over a 6-month period to facilitate an increase in methylation of the ASC gene in comparison to a control. Downregulation of this gene through methylation inversely results in decreased expression of the ASC protein. This is important as the ASC protein is a mediator of the cytosol-type inflammatory signaling pathway and in toll-like receptor (TLR) signaling, and ultimately an initiator of innate immunity. However, upregulation of this protein is associated with increased cleaving of inflammatory cytokines, such as IL-1β, IL-18, IL-6, IL-8, and IL-10, as well as TNF-α through interaction with caspase-1. Increased cleaving of these cytokines can interfere with cell-mediated immunity and chronic inflammation, both responsible for tumor growth. The study conducted by Nakajima et al. also looked at the effects of the same exercise protocol on the tumor suppressor gene, p15. The results of this study indicate no significant change in p15 methylation status. Methylation of p15 is associated with uninhibited expression of transforming growth factor – β, and is found is many types of cancer. However, p15 downregulation or deletion is often found in conjunction with p16 alterations, making it difficult to discern any importance of the findings regarding this gene independently by Nakajima et al.[12, 13]
Looking specifically at breast cancer risk, a cross-sectional study conducted by Coyle et al. of exercise levels in pre- and post-menopausal women without breast cancer, determined that physical activity over the lifetime, over the previous 5 years, and the previous year were all inversely related to hypermethylation of the APC gene, though not in a statistically significant manner. APC is a tumor suppressor gene that becomes silenced following hypermethylation and, in addition to RASSF1A, is important indicator of the number of benign breast biopsies, a predictor for breast cancer risk. The authors of this study suggest that decreased hypermethylation of APC is due to decreased circulating estrogen levels as result of increased physical activity. The exact mechanism of this relationship is unknown, but further evidence exists in animal models in which estrogen dosage, of estradiol and diethylstilbestrol, increased methylation of E-cadherin and p16 tumor suppressor genes in the benign breast cells of mice.
The above studies[11, 12] indicate a potential link between physical activity and the reduction of aberrant methylation of tumor suppressor and proto-oncogenes in non-cancerous populations. It would appear that a moderate-intensity exercise program consisting of interval walking at 40 and 70% of peak aerobic capacity, conducted for at least 26 minutes per day, for at minimum 1 year, would be sufficient to lower the risk of breast cancer development via DNA methylation.[11, 12] The daily dose of exercise has been confirmed by Zhang et al, in which they found that healthy individuals who exercised 26 to 30 minutes per day resulted in greater leukocyte DNA methylation, which is associated with decreased risk of multiple cancer types, compared to those who exercised less than or equal to 10 minutes per day. In the Nakajima et al study, the identified the acceptable weekly exercise dose as at least 2 days per week. Zhang et al failed to make this distinction, however, but statistical analysis methods suggest that the exercise dose should be recommended daily. While this data provides adequate evidence to suggest exercise as a preventative intervention to cancer development, there is insufficient literature to substantiate these findings in reversing DNA methylation in patients already diagnosed with cancer.
b. Hormones, Exercise, and Risk Reduction
A reduction in postmenopausal breast cancer risk is associated with a decrease in obesity and increase in physical activity. One main mechanism for this decrease in risk is through a decrease in serum sex hormones and an increase in sex hormone-binding globulin (SHBG). Increased levels of estrogen and androgen are strongly correlated to increased breast cancer risk as estrogen is responsible for increased tumor proliferation in estrogen receptor positive breast cancer. SHBG inhibits the function of estrogen by binding to it.[16, 17, 18] In a study by McTiernan et al., higher body mass indexes (BMI) are positively associated with levels of estrone, estradiol, free estradiol, free testosterone, and prolactin and negatively associated with SHGB in 267 postmenopausal women. The study also found a negative correlation between physical activity and levels of estrone, estradiol, and free estradiol. A randomly controlled trial by Friedenreich et al.  of 320 sedentary postmenopausal women between the ages of 50-74 who performed 45 minutes of aerobic activity five times a week at 70-80% heart rate reserve supported this finding. There was a significant decrease in estradiol and free estradiol and a significant increase in SHBG after 12 months of the intervention. A positive correlation was also found between exercise adherence and percent change in estradiol. This study did not find a change in androgen levels with exercise, but it has been postulated that decreasing body fat reduces the conversion of androgen to estrogen by decreasing the available tissue able to convert androgens to estrogen as seen in Figure 1.[16, 17, 20] Furthermore, another study found significant decrease in androgen levels in an exercise group who lost more than 2% body fat, but no significant decreases in estrogen levels.  This study involved 189 sedentary, postmenopausal women with an intervention of 1 year combined aerobic and strengthening exercises for 2.5 hours a week at 60-85% max heart rate. A study by Nichols et al.  of 3,993 women with invasive nonmetastatic breast cancer, followed for a mean of 6.3 years had a 13% increase in breast cancer-specific mortality for every 5kg of weight gain post diagnosis. These findings suggest the levels of circulating estrogen and androgen can be decreased to reduce breast cancer risk through physical activity and reduction of body fat.
Despite the role of the reduction of adipose tissue in reducing circulating estrogen, a pure exercise effect has been seen in the reduction of insulin levels, which increases SHBG levels and decreases production of estradiol.  Increased levels of insulin and insulin-like growth factor-1 (IGF-1) have been proven to increase the risk of the recurrence of breast cancer and death. IGF-1’s primary binding protein, IGFBP-3 is also associated with increase recurrence of breast cancer and high levels are seen in breast tissue with poorer prognosis. Additionally, higher levels of insulin are strongly correlated with obesity and low physical activity, which both indicate a negative prognosis for breast cancer. Decreasing insulin levels by 25% has been linked to a 5% decrease in breast cancer risk, which is the same benefit seen from adjuvant chemotherapy.  A randomized controlled trial by Irwin et al , looked at the effects of 150 weekly minutes (5-30 min sessions) of moderate intensity aerobic exercise for 6 months on sedentary postmenopausal women who were diagnosed with stage 0-IIIA breast cancer. The study showed significant decreases in IGF-1 and IGFBP-3 in the exercise group compared to increases in the control group. Furthermore, a 20.7% between-group difference was seen in insulin levels, although this was borderline significant. A significant finding of the study was the 9% between-group difference in IGF-1 levels, which correlates to half the change seen with a 20 mg/d dose of tamoxifen. This is clinically meaningful as cellular changes can be seen with exercise instead of pharmaceutical interventions. Another study by Ligibel et al, showed a 28% reduction in insulin levels with a 50 minute strength training session twice a week and 90 minute home aerobic programs for 16 weeks compared to a 3% decrease in the control group. This study involved 101 sedentary, overweight women who were previously diagnosed with breast cancer. However, studies on women who were more active and leaner, did not show significant decreases in the above levels leading one to believe exercise is more effective at reducing already higher insulin levels in sedentary, obese women.
Figure 1 -Obesity and Breast Cancer Link 
c. Mechanisms that May Contribute to Risk Reduction
A summary of proposed cell biology mechanisms for breast cancer risk reduction with exercise is presented in the table below. Data is drawn from the research presented above as well as additional mechanisms suggested by Miller in his 2010 book.
|Cell Biology Mechanism||Effect of Mechanism on Breast Cancer||Effect of Exercise on Mechanism||Proposed Effect of Exercise on Breast Cancer Risk|
|Sex Hormones||Sex hormones increase cell proliferation and decrease apoptosis, increasing the chance that abnormal cells will proliferate unchecked thus increasing the risk of developing a breast tumor||Decreases ovarian and fat-produced estrogen and increases sex hormone-binding globulin (SHBG) which decreases estrogen and testosterone available in the bloodstream||Reducing levels of circulating sex hormones leads to decreased cell proliferation and increased cell apoptosis in the breast. Therefore, it is more difficult for abnormal cells to develop into a tumor, effectively decreasing the risk of breast cancer. As sex hormones can also feed into estrogen-positive tumors, decreasing levels of circulating estrogen through exercise may also help decrease the growth rate of tumors that are estrogen-receptor positive.|
|Insulin & IGFs||Increase circulating sex hormone and cell proliferation||Increases delivery of glucose to the muscles, elimination of free fatty acids from the system, glucose transporter protein and mRNA, and post-receptor insulin signaling||Decreases breast cancer risk by decreasing rate of cell proliferation and reducing levels of sex hormones in the bloodstream (see entry on Sex Hormones above)|
|Body Fat||Adipose tissue stores carcinogens, increases sex hormones, and increases insulin, all increasing the risk of breast cancer||Results in body fat reduction||Decreases the levels of carcinogens stored in the body, making resultant mutations that may turn into breast cancer less likely. Additionally decreases the levels of sex hormones and insulin available in the bloodstream (see entries on Sex Hormones and Insulin above).|
|Immune Function||Proper immune function will eliminate abnormal cells which may develop into breast cancer||Moderate physical activity increases macrophage activity, lymphokine-activated killer cells, and lymphocyte proliferation, though intense physical activity may depress the immune system||An activated immune system will better detect and destroy abnormal cells, decreasing the likelihood they will develop into a breast tumor|
|Adipocytokines||Stimulate angiogenesis and estrogen biosynthesis, feeding into potential tumors and allowing them to develop and grow||Decreases TNF-alpha, leptin, CRP, and IL-6||Reduces estrogen in the bloodstream (see Sex Hormones above) and reduces angiogenesis. See Cytokines below for additional information.|
|Antioxidant Defense||Reduction of free radical-induced DNA damage decreases the likelihood of a mutation that can develop into breast cancer||Upregulates free radical scavenger enzymes and antioxidant levels to improve DNA repair and free radical defenses||Enhanced antioxidant defense due to exercise further improves the effectiveness against development of breast cancer and decreases the risk of a tumor.|
It should be noted that, in theory, exhaustive or intensive exercise should increase risk of developing breast cancer due to the negative effects of intense exercise on the immune system (immune surveillance theory). However, there is little actual evidence of increased development of breast cancer following intensive exercise regimens; current evidence maintains a full inverse relationship between exercise and breast cancer, with increasing physical activity leading to decreased risk of malignancy.
d. Exercise Prescription Recommendations to Lower Risk
In order to make meaningful changes on the above cell mechanisms to significantly reduce the risk of breast cancer, it is recommended that individuals exercise at least 26 minutes per day at 70% heart rate reserve, most or all days of the week. Ideally, the combined weekly total should be greater than or equal to 150 minutes of exercise. These recommendations were developed by combining protocols of the above exercise studies showing positive benefits in breast cancer risk reduction. Evidence has shown that these exercise recommendations should result in DNA methylation of proto-oncogenes and leukocytes, reduced circulating sex hormones, increased SHBG levels, decreased body fat percentage, decreased insulin, and decreased levels of IGF-1. Additional reductions in insulin levels may be gained by strength training twice per week. While antioxidant defense and adipocytokines may also be positively affected by this exercise prescription, they have not been researched closely enough to definitively ensure positive benefits will result by following these recommendations.
3. Fatigue and Exercise
Cancer-related fatigue (CRF) is a predominant and functionally-limiting component of breast cancer treatment. CRF is characterized as being disproportionate to level of exertion and unaffected by rest. While an exact mechanism of CRF is not clear, several hypotheses including serotonin dysregulation, hypothalamus-pituitary-adrenal axis dysfunction and cytokine proliferation have been discussed in the literature.
The cellular mechanisms for cancer-related fatigue (CRF) are not readily understood at this point in time. However, it is thought that activation of the immune system, and the pro-inflammatory cytokines in response to that activation, may play a role in the fatigue process. The cytokines of particular interest are interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), because these cytokines tend to have many peripheral and central effects that contribute to host defense, including effects on energy. Skeletal muscle selectively produces IL-6 during exercise and IL-6 can decrease the production and activity of IL-1β and TNF-α. Levels of IL-6 elevate rapidly during exercise and reduce to baseline after completion. Increased levels of IL-6 and IL-1β and decreased levels of TNF-α promote tumor proliferation in breast cancer as seen in the Cytokines section. It is theorized that this cascade is responsible for the reason that exercise decreases CRF. An animal study found that injecting IL-1β, TNF-α, or lipopolysaccharide (an inducer of synthesis of IL-1β and TNF-α) leads to many negative effects, including fatigue. In addition, cancer patients who are treated with cytokine therapy have demonstrated increased fatigue in conjunction with flu-like symptoms (lethargy, depressed mood, and cognitive disturbances). In a quantitative review of patients with cancer, a significant correlation was found between fatigue and the circulating levels of IL-6 and IL-1. A study by Bower et al. looked at this possible association and found that breast cancer survivors with CRF were significantly more likely to have higher serum levels of pro-inflammatory cytokines when compared to breast cancer survivors who did not have CRF. The particular cytokines that they found elevated were interleukin-1 receptor antagonist, soluble tumor necrosis factor receptor type II (TNF-RII), and neopterin. Soluble TNF-RII is typically released by monocytes/macrophages and lymphocytes when TNF-α is produced, thus soluble TNF-RII levels are highly correlated with TNF-α level in serum and reflect their activity. Studies done in normal individuals show exercise reduces the expression of TLR4 and in turn lowers the production of IL1β, IL6 and TNF-α. This could be a factor in decreasing CRF through exercise.
While the specific underlying mechanisms are unknown, there are randomized control trials that display strong support that aerobic exercise can reduce CRF as seen in the chart below. Specific studies on how exercise affects the production of cytokines in relation to breast cancer are hard to find; however, there are studies on individuals who have chronic conditions such as obesity, heart failure, and metabolic syndromes, all of which are known to be characterized by increased circulating pro-inflammatory cytokines and other inflammatory markers. These intervention studies indicate that in some cases exercise alone or in combination with diet can reduce the levels of circulating IL-6 and/or TNF-α. Reduced levels of IL-6 are beneficial in breast cancer patients as IL-6 promotes tumor growth , however, reduced levels of TNF-α are indicated in tumor growth and tumor angiogenesis. In healthy individuals, studies show increased levels of circulating IL-6 released periodically from skeletal muscle during intense exercise, have strong anti-inflammatory effects due to inhibition of TNF-α production and generation of IL10 and IL-1RA. Yet these responses cannot solely explain why exercise is beneficial in decreasing cancer fatigue. This is especially true with advanced cancer cases where less intensive exercise is recommended and activity may in fact be detrimental if excessive.
The same cytokines thought to play a role in CRF are also thought to be responsible for poor sleeping quality in cancer patients. Radiation therapy is a common breast cancer treatment and has been found to increase levels of IL-6 and TNF-α, thus activating the inflammatory pathways of the central nervous system. TNF-α activity will promote inflammation, and low sustained levels are found to promote tumor angiogenesis in cancer patients. IL-6 can either be pro- or anti-inflammatory dependent on the stimulus. If there is a local tissue injury, like in radiation therapy, it acts as a pro-inflammatory cytokine at that site. This is considered a low grade inflammatory response that is an acute-phase response, which in the case of release of these two cytokines is not a desired effect. As previously mentioned, the release of IL-6 and TNF-α acting as pro-inflammatory cytokines have been found to be associated with fever, pain, cognitive impairment, fatigue, insomnia, and decreased eating. This is why it has been postulated that cytokines play a role in both sleep deprivation and CRF. They also have a part in sleep regulation by their interaction with the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is responsible for initiating the secretion of cortisol, which is a sleep-regulated glucocorticoid. Both IL-6 and TNF-α can activate the HPA axis, leading to the secretion of cortisol. Abnormal cortisol fluctuations can be a result of high circulating levels of cytokines. Abnormal cortisol secretions are associated with shorter sleep duration and higher sleep disturbance, thus linking the treatment of cancer and increased levels of cytokines to sleep. The study by Sprod et al. shows this link and is listed in the table below. Cortisol also stimulates the production of IL-1RA and IL-10.  These cytokines are unfavorable in breast cancer as IL-1RA competes with IL-1β (a tumor suppressor) for a binding site and IL-10 plays a role in tumorigenicity.  
|Authors||Type of Study||Subjects||Exercise Intervention||Cytokines Measured||Intervention Effects/Results|
|Wood LJ, Nail LM, and Winters KA||Review Article||Cancer patients||To review evidence that muscle-derived interleukin-6 (IL-6) mediates some of the beneficial effects of exercise on cancer treatment-related fatigue (CTRF)||IL-6, TNF-α, and IL-1β||Inconclusive findings, further research is indicated to determine whether the anti-inflammatory effects of exercise are the reason for the reduction of fatigue in cancer patients.|
|Sprod LK et al.||Randomized Control Trial||Breast and prostate early stage cancer patients with no metastasis.||Compared the influence of a home-based exercise intervention with standard care/control on sleep quality and mediators of sleep. Breast and prostate cancer patients (n = 38) beginning radiation therapy were randomized to a 4-week exercise program or no exercise arm. Cardiovascular work- Walking program using pedometers in which after averaging steps per participant the first week, they were told to increase steps by 5-20% each day during a moderately intense exercise. Used ACSM modified RPE scale of 1-10; target was to work at 3-5 RPE level. Resistance training- Do 7 days a week at low to moderate intensity using therabands. Increasing resistance by shortening band or new color to eventually reach goal of 4 sets of 15 reps.||IL-6, TNF-α, and soluble tumor necrosis factor-alpha receptor (sTNF-R)||IL-6 levels were significantly lower in the exercise group and there was an association found between high levels of IL-6 and decreased sleep duration in the control group. This suggest higher levels of IL-6 are associated with impaired sleep duration. Also, in both groups, higher fasting IL-6 levels were correlated with reduced sleep and sleep efficiency. TNF-α was lower in the exercise group, but not significantly. sTNF-R was decreased by 80pg/mL in the exercise group and increased by 20 pg/mL in the control group. There was a positive association found between sTNF-R and sleep quality, suggesting sTNF-R plays a role in sleep depredation.|
|Payne et al. ||Longitudinal Randomized Controlled Trial||20 women with breast cancer older than 55 years old receiving hormonal therapy||Exercise Group: Moderate walking activity for 20 minutes, 4 times a week; Control group: Usual care||IL-6, cortisol, serotonin and bilirubin||No significant difference between groups was found in IL-6 levels. A downward trend was found in cortisol levels for the exercise group, but was not significant. Serotonin and bilirubin were also found to have a weak intervention effect with the effect being significant in serotonin levels.|
|Bower et al.||Outcome Measures Study||40 breast cancer survivors. 20 who reported fatigue and 20 who did not report fatigue||No intervention was implemented. Purpose of the study was to see if fatigued breast cancer survivors had increased levels of cytokines compared to non-fatigued survivors.||IL-1β, IL-1ra, sTNF-RII, and neopterin||Results showed that fatigued women had significantly higher serum levels of IL-1ra, sTNF-RII, and neopterin than non-fatigued women. There were no group differences found for IL-1β; however, the study stated that serum levels of IL-1 were very low in their sample of women and fell outside of the detectable range for almost half of the study participants.|
b. Serotonin (5-HT) Dysregulation
Brain serotonin (5-HT) dysregulation has been described as a possible contributor to CRF in individuals with breast cancer.[28, ] Increased levels of tryptophan, the precursor of 5-HT, have been noted with exercise leading to increased concentrations of 5-HT in animals. These increased levels of 5-HT have been implicated in physical and mental fatigue following strenuous exercise as well as conditions such as chronic fatigue syndrome.[28, 41] The mechanism by which tryptophan enters the brain in humans is unknown. [28, 42] It is thought that tryptophan competes with branched-chain amino acids (BCAAs) for transporter molecules across the blood-brain barrier.  It has also been suggested that increased BCAA uptake by muscle cells with exercise allows for increased levels of tryptophan centrally.  Multiple animal studies have investigated the impact of exercise on 5-HT levels. One such study conducted by Bailey and colleagues  considered the impact of 5-HT levels on performance during prolonged (20 m/min for 60 min) or exhaustive exercise (20 m/min to exhaustion) in rats. 5-HT levels were significantly increased compared resting controls after 60 minutes of exercise. Additionally, rats injected with 5-HT antagonist exercised 26% longer during exhaustive trial than non-injected rats. This is indicative of the role of 5-HT in contributing to fatigue. 5-HT concentration may become dysregulated as outlined below, with symptoms that manifest as severe fatigue similar to chronic fatigue syndrome.
Evidence exists that the proinflammatory cytokine tumor necrosis factor α (TNF-α) influences 5-HT metabolism by increasing its release into the synaptic space as well as increasing its transporter function, thus effectively increasing 5-HT clearance. Additionally, 5-HT is capable of decreasing TNF-α synthesis, thus creating a negative feedback loop. It is thought that this feedback loop may become dysregulated in cancer or in response to therapies. 
It must be noted that much of the evidence implicating 5-HT dysregulation in the existance of cancer-related fatigue (CRF) is theoretical and based on rat models of exercise. No studies have been conducted investigating the relationship between 5-HT concentrations and exercise performance in individuals with breast cancer. Further research is necessary to delineate the causes of CRF.
c. Exercise Prescription Recommendations for Fatigue
When presenting exercise recommendations based on the cellular mechanisms of cytokines it is difficult to suggest specific guidelines. While exercise has been shown to decrease CRF, the cellular mechanisms are not well understood. Cytokines have been thought to be one of the reasons breast cancer patients and survivors show decreased fatigue levels with exercise. Research does not denounce this theory, nor does it strongly support it.
The study by Bower et al. demonstrate that breast cancer survivors who report fatigue have higher levels of certain cytokines. Then the randomized control trial by Sprod LK et al. shows that low to moderate intensity aerobic and resistance training can decrease IL-6 levels without significantly decreasing TNF-α. This is important because, as previously mentioned, reduced levels of IL-6 are beneficial to cancer patients, but if TNF-α is significantly reduced it might actually have a negative effect in promoting tumor growth and angiogenesis. Based off of this information and favorable outcomes found in the study by Sprod LK et al., a proposed recommendation could be based off of their study. The ASCM exercise guidelines for cancer patients listed in a table in the introduction closely follow the exercise prescription seen in this study as well. This theoretically provides credibility based on cellular cytokine levels to the recommendation.
4. Exercise for Tumor Cell Proliferation and Death
a. Oxidative Stress and Lipid Peroxidation
Oxidative stress is a known mechanism in cancer proliferation and development in which oxidative damage occurs to DNA structure, silencing tumor-suppressor genes and activating tumor promoting genes.  With increased oxidative stress, come subsequent increases in reactive oxygen species. The reactive oxygen species (ROS) can oxidize lipid components from cell membranes, a process called lipid peroxidation, resulting in damage to many cellular structures and mechanisms. Lipid peroxidation has been found to be increased in human breast cancer cells.  With this increase in lipid peroxidation was an increase in anti-oxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), and glutathione S-transferase (GST).  It is suggested that these increases in anti-oxidant levels allows the cells a selective advantage by escaping detection by cytotoxic lymphocytes.  There is literature, however, that suggests lipid peroxidation and oxidative stress mechanisms may also provide a method of limiting tumor cell proliferation. [46, 48]
i. In Vitro Evidence
In a study conducted by Cipak et al. , breast cancer was cultured in the collagen of raw calf hide, with the collagen either normal or treated with the hydroxyl (OH-) ROS. The importance of collagen protein in this study is to highlight its interaction in the extracellular matrix (ECM) with breast cancer stem cells (CSCs).  This interaction is fundamentally the microenvironment for the growth and dissemination of CSCs, through bone marrow, allowing proliferation and metastases despite surgical removal of the primary tumor in advanced stages.  In the ECM, collagen type I forms a biological barrier to defend against pathological processes and molecules. In cancer, tumor cells penetrate this barrier by protease-dependent invasion, where secretion of matrix metalloproteinase degrades the collagen, and by protease-independent invasion, where tumor cells physically break through the barrier by amoeboid-like properties.  It is understood that ECM proteins can be affected by oxidative stress and therefore effect the microenvironment harvesting CSCs.  A lipid peroxidation byproduct and potential signaling molecule, trans-4-hydroxy-2-nonenal (HNE), was a focal marker of the Cipak et al. study, in which HNE can function as growth regulatory or cytotoxic depending on concentration levels. In this study , CSC viability was increased while simultaneously reducing cytotoxicity of HNE. Comparatively, when treating the oxidized collagen, the CSCs demonstrated a decrease in viability and could not prevent cytotoxicity of HNE. The exact mechanism is unknown, but one proposed mechanism for this is that HNE has an affinity to amino acids, which may be lacking in the CSCs, preventing binding of the two molecules.  These findings indicate that increased lipid peroxidation through increased oxidative stress may be beneficial in regulating tumor cell proliferation and growth.
ii. In Vivo Evidence
In a study conducted by Radak et al. , 21 first-generation hybrid BDF1, female mice received transplanted leukemia cells and were divided into control, exercise-trained mice who did not exercise during leukemia, and exercise-trained mice who exercised with leukemia. The exercise protocol consisted of 5, 1 hour swimming sessions per week, for 10 weeks. Radak et al.  found that the tumor size in the mice who continued to exercise with leukemia had a tumor size reduction by nearly 50% compared to the controls and exercise-trained who did not continue to exercise 18 days post-transplantation. It was also found that the tumor growth rate was significantly reduced during the final 4 days of the study compared to the other groups. Interestingly, it was found that anti-oxidant enzyme activity did not change, but decreased reactive carbonyl derivatives (RCDs) and increased lipid peroxidation was found in the smaller tumors of the exercise group.  RCDs are a product oxidative damage via free radicals on amino groups in proteins and are indicative of ROS concentration. Decreased RCDs should inherently mean that there was decreased ROS production, but the increase in lipid peroxidation suggests that the decrease is due to other mechanisms not fully understood.  Another interesting finding was that ROS formation was not significantly increased. This finding was investigated by quantifying the concentration of redox-sensitive proteins p53, Ras, and I-κB that may be induced by ROS activity. It was found that Ras, a protoncogene protein, and I-κB were increased in the exercise group tumors. It was suggested that Ras activated downstream mitogen-activated protein kinase cascades (MAPK), ultimately activating nuclear factor-κB (NF-κB), which can be used as indicator of transcription rate.  Increased activation of NF-κB is associated with increased ubiquination of I-κB, which does not coincide with the findings of the study. Therefore, dissociation between I-κB and NF-κB has likely occurred, but there is increased expression of I-κB.  I-κB, which renders NF-κB inactive, is also produced by NF-κB activity. Therefore, it likely that ROS production is leading to dissociation of NF-κB and I-κB, causing increased expression of active I-κB, that may attenuated the cell growth cycle during the transcription stage. The findings of this study suggest a different mechanism than the in vitro study, but provide an example of oxidative stress restricting tumor cell proliferation.
b. Apoptosis Pathways
While it has been established that inducing oxidative stress can effect tumor cell proliferation through cytotoxicity of cancer stem cells by HNE during an in vitro study  and through dissociation of I-κB and NF-κB in an in vivo model , it is unclear how oxidative stress affects cycle growth cycles to induce apoptosis. One in vivo model  suggests that a potential mechanism involves mitochondrial (intrinsic) apoptosis signaled by increase energy expenditure with subsequent energy intake reduction.
i. In Vivo Evidence
In a study conducted by Zhu et al. , 90 Sprague Dawley rats were injected with 1-methyl1-1-nitrosourea (MNU), a model for breast cancer, and were randomized into sedentary (SC), reduced dietary intake (RE), and physical activity (PA) groups. The rats in the physical activity group were given unrestricted access to a motorized running wheel, with a food reward determined from the amount of physical activity. The average distance ran per day in the exercise group was 5,048 meters (3.14 miles) at a moderate intensity.  The physical activity group demonstrated greater reductions in cancer incidence (66%), cancer multiplicity (1.62), and cancer latency (45 days). It should be noted that similar, but lesser, significant findings were also correlated with the reduced energy intake group compared to controls.  Looking at cell proliferation, RE and PA groups demonstrated a mild decrease in growth fraction, as well as increases hypophosphorylated protein Rb and decreases in the protein E2F-1.  E2F-1 is a transcription factor important promoting expression of genes responsible for DNA synthesis and the regulation of the G1/S transition during the cell cycle.  Rb, or retinoblastoma protein, possesses tumor suppressor qualities by inhibiting cell cycle progression. Hypophosphorylated Rb binds E2F-1 until it undergoes phosphorylation, releasing E2F-1, and allowing progression from the G1 to S phase of the cell cycle.  Therefore increased hypophosphorylated Rb decreased the amount of active E2F-1, and inhibiting the cell cycle during this transition phase.
Zhu et al.  also found increased apoptotic activity, though not statistically significant, in the PA and RE groups. Particularly important, was the two-fold increase of caspase 3. Caspase 3 is the downstream mediator of the execution phase of intrinsic and extrinsic apoptosis pathways. Coinciding with this finding was that there was increase in expression of Bax and Apaf proteins, with a decrease in Bcl-2 and XIAP proteins.  XIAP is an inhibitor of apoptosis protein (IAP) that inhibits apoptotic caspases, including 3 and 9, and Bcl-2 inhibits the protein Bax before it can interact with cytochrome c within the intrinsic apoptosis pathway.  Bax (Bcl-2 associated X protein) is a pro-apoptotic protein upregulated by p53, a tumor suppressor protein, which is activated in response to stress. It is also suggested to have a role in opening of pores in the mitochondrial membrane, releasing cytochrome c into the cytosol.  Lastly, Apaf (or Apaf-1) is a pro-apoptotic protein that binds cytochrome c and dATP to form an apoptosome, a structure that, through binding and cleaving, activates caspase 9.  The upregulation (or downregulation) of these particular proteins indicate an activation of the mitochondrial, or intrinsic, apoptosis pathway within breast cancer cells. The signaling mechanism that leads to this cascade is not fully understood. Based on the study design, it is difficult to discern if the results were due more to increased exercise or reduced energy intake. Greater energy intake compared to the RE group indicates that physical activity plays some part in inducing apoptosis and halting the cell cycle. Additional findings from Zhu et al.  examine the effects on angiogenesis, which is discussed elsewhere.
c. Protein Kinases and Signal Transduction
5'-AMP-activated protein kinase (AMPK) has been shown to inhibit expression and activity of enzymes associated with cancer proliferation, such as FAS and mTOR. Therefore AMPK has been shown to inhibit the growth of some cancer cells in vitro. This pathway involves LKB1 as an upstream activation of AMPK, and TCS2 as a downstream effector of AMPK, with each proven to be tumor suppressors. TSC2 is phosphorylated and activated by AMPK to negatively regulate protein synthesis by inhibiting mTOR. Both calorie restriction and exercise have proven to increase AMPK activation, as well as diminishing insulin resistance and the pro-inflammatory response in obesity and type 2 diabetes. However, this increase in AMPK activation also appears to reduce the incidence of some cancers, including breast cancer. It has also been proven that overexpression of alpha and beta subunits of AMPK, activated by AICAR and metformin, inhibit both growth and survival of some cancer cells. 
In a study of changes in insulin signaling in skeletal muscle, low to moderate intensity (20-30 min at 50% VO2 max) aerobic exercise induced an isoform specific increase in AMPK alpha-2 activity. Another study also observed increases in AMPK alpha-1 and alpha-2 isoforms following anaerobic sprint exercises (30s sprints on bicycle ergometer).  Although these studies are not directly proven to inhibit breast cancer proliferation, it can be inferred that a similar exercise program may be useful in treating those with the disease. The increase in AMPK activity would indicate an increase in tumor supressor pathways to decrease the growth and spread of cancer cells, and increasing the effectiveness of treatment.
Limited research is available looking at the formation or the degeneration of tumor blood vessels. In a study conducted by Zhu et al.  found that moderate intensity, running exercise in MNU-injected Dawley rats (see Apoptosis Pathways above) demonstrated reduced vascular density in mammary tumors. It was determined that there was little effect on smaller vessels, classified as category 1, but larger vessels (greater than category 1) demonstrated decreased density, and there was on overall reduction in number of blood vessels and in blood vessel area.  Consistent with these findings was that vascular endothelial growth factor (VEGF) was diminished compared to sedentary controls. VEGF is an extracellular protein that binds to tyrosine kinase membrane receptors, allowing for signaling of the DNA to induce vasculogenesis by increased production of endothelial cells. Decreased VEGF would therefore deprive tumor cells of the necessary blood supply to proliferate. The difficulty with discerning between reduced energy intake and physical activity effects has been noted elsewhere in this document (See Apoptosis Pathways), but the effects on blood vessel density and concentration is a particularly interesting finding considering that angiogenesis is increased in normal skeletal muscle tissue in response to exercise. 
e. Exercise Prescription Recommendations for Tumor Proliferation
The above studies indicate that aerobic exercise of moderate intensity for up to 1 hour, 5 to 7 days a week can induce specific cellular mechanisms that can slow or impair tumor cell growth, or initiate tumor cell death. These recommendations were synthesized from the above protocols where aerobic exercise resulted in the induction of lipid peroxidation, oxidative stress, and intrinsic apoptosis. Oxidative and subsequent lipid peroxidation was shown to increase the cytotoxicity of HNE to breast cancer stem cells, disrupt the cell growth cycle as the G1/S transition phase, increase Bax and Apaf-1 pro-apoptotic proteins leading to cancer cell death, and decrease tumor angiogenesis by decreasing VEGF. Lastly, this intensity of exercise been found to inhibit intra- and intercellular communication of growth factor signals in some cancer cells through increased activation of the AMPK pathway.
5. Adjuvant Treatment
Cancer survival rates have increased significantly in recent decades. A large part of this is due advancements in surgical technique and increased use of adjuvant therapies such as chemotherapy, radiotherapy, and hormonal therapy. With these treatments come significant side effects, many of which can reduced via exercise. In recent years extensive research has emerged that physical activity during cancer treatment; including radiation, chemotherapy, and hormonal therapy is safe. In many studies exercise was found not only safe, but beneficial to patients undergoing treatment for breast cancer.
Chemotherapy has been associated with potential long-term negative side effects including, weight gain, cardiac dysfunction, fatigue, anxiety, depression, and premature menopause. Long term immunosuppression has also been observed.
i. Weight gain
A study by Courneya et al. showed that structured exercise programs including moderate intensity resistance and aerobic exercise have elicited positive treatment effects in terms of maintaining bodyfat levels, lean muscle mass, aerobic fitness, and muscular strength. In addition, self esteem and chemotherapy completion rates improved among the exercise group. These areas showed negative changes in the control groups. Based on this finding it would appear that exercise helps the patient preserve their physical and psychological status while undergoing chemotherapy rather than experience the negative impact chemotherapy treatment typically has in these areas. No lymphedema or other adverse effects were noted.
ii. Cardiac Dysfunction
The reason behind the cardiac decline while undergoing chemotherapy (particularly anthracyclines) is thought to be related to myocardial cell death in the wake of increased free radical production secondary to the chemotheraputic agent. Aerobic and resistive exercise can potentially reduce this negative consequence to the cardiac musculature. In turn this allows the patient to remain more active, which can then help offset muscle loss, prevent weight gain, and assist in feelings of well being and heightened self-esteem.
Chemotherapy related fatigue can potentially be reduced via regulation of cytokine release, particularly the regulation of IL-6, which has been shown to be related to a proinflammatory response and its resultant fatigue.  Details of this process can be found here.
iv. Premature Menopause
Premature menopause is not as readily affected via exercise as the chemotheraputic agent directly attacks the ovaries and the follicular reserves (eggs) within. Alkylating agents, platinum agents, and taxanes pose the biggest threat to fertility in those undergoing chemotherapy. A currently emerging treatment designed to preserve ovarian function in women undergoing chemotherapy is the administration of gonadotropin-releasing hormone agonists (GnRHa). This is not a novel treatment for breast cancer patients and is related to an established form of hormonal treatment utilized in estrogen positive (ER+) breast cancers known as LHRH agonist therapy. GnRHa’s purported fertility protecting characteristics when used in conjunction with chemotherapy is a recent discovery. GnRHa use has been linked to negative cardiac side effects in women including decreased stroke volume, decreased heart rate, and decreased peak flow velocity. The specific mechanism is not fully known but is thought to be related to the role GnRH plays in cardiac muscle cell contraction via its interaction with the Protein Kinase-A(PKA) mediated pathway. In the presence of GnRHa the normal hormonal equilibrium is disrupted and intracellular calcium in the cardiac muscle cells decreases and cardiac contractility is decreased. Based on this idea, the cardiac benefits offered by exercise, particularly an improvement in cardiac function and contractility, could be of benefit to a patient undergoing GnRHa therapy, particularly if initiated prior to treatment.
As chemotherapy drugs are non-specific, chemotherapeutic agents typically harm other cells in the body besides cancer cells, such as B and T lymphocytes. CD4+ T-helper cells have been shown to be the slowest lymphocyte to recover after chemotherapy; in 1997, researchers demonstrated CD4+ T-cells decreased during chemotherapy by more than 60% and were still below normal levels after 18 months.
One randomized controlled trial demonstrated the results of exercise on CD4+ T-cells in women with breast cancer post-chemotherapy. There were 2 groups of participants, exercisers (N=28) and non-exercisers (N=21). Patients underwent the intervention 2 weeks or up to 2 months after a chemotherapy treatment. The exercise group met with a trainer for one-on-one sessions 3x/week for 3 months. 12 participants in the exercise group worked for only 3 months, 10 participants worked out for an additional 3 months with the trainer, and 6 worked out for an additional 3 months at home. The exercise consisted of a 5-minute warm-up, resistance training with Flexbands, and aerobic activity such as running or walking, with total sessions lasting from 40 to 90 minutes. Aerobic training progressed from 10-20 minutes to 20 minutes at 60-75% of functional capacity. The control group participants were asked not to change their exercise habits for the 6 months.
Blood samples were taken before chemotherapy, after chemotherapy before the exercise intervention began, after 3 months of exercise, and after 6 months of exercise. Results showed that there were no differences in the mean levels of CD3+, CD4+, CD8+, B, or NK cells between exercise and control groups. At every blood draw following chemotherapy, CD3+, CD8+, NK, and B-cell levels were significantly reduced in both groups. Exercisers did, however, show a larger percentage of proliferating CD4+CD69+ T-helper cell when compared with the non-exercisers, even though the levels were still below normal values. Values were improved in the groups who exercised for 6 months rather than just 3 months. This indicates that the exercise intervention may help immuno-compromised breast cancer patients post-chemotherapy with immune responses to prevent complications like secondary infections.
Common side effects of radiation therapy include fatigue, lymphedema, and pulmonary toxicities. Multiple studies have shown that exercise evokes positive outcomes in patients undergoing radiation therapy in terms of quality of life, and specifics as to how it can impact specific side effects are continually emerging.
As seen in chemotherapy, fatigue is thought to be related to the actions of proinflammatory cytokines which have also been associated with fever, pain, cognitive impairment, insomnia, and decreased eating. Some studies imply that exercise can have a positive effect due to its ability to attenuate the proinflammatory cytokine effects and lessen the activation of the HPA axis and resultant cortisol production. Details of this process are contained in the cytokine section above.
Breast cancer-related lymphedema (BCRL) is an atypical accumulation of fluid rich in protein in the limb caused by an increase in osmotic pressure moving fluid into the interstitial space. BCRL causes edema of the limb, pain, tightness and heaviness that interferes with functional use of the arm. BCRL occurs in 2.4% to 49% of women with 10-30% occurring after axillary lymph node dissection. BCRL can appear immediately after surgery until 28 weeks later.   The etiology of BCRL is not fully understood and multifactorial. There are conflicting results as to whether exercise is effective in reducing the incidence of BCRL.  A review by Chan et al  found that exercise commencing immediately post-surgery did not increase surgical complications and shoulder range of motion significantly increased. However, early onset of exercise did not affect the incidence of post-surgical lymphedema. 
iii. Pulmonary Toxicity
Pulmonary toxicity related to cancer treatment occurs when localized radiation damages lung tissue in the corresponding area via the same mechanism that it disrupts oncogenic tissue.. This can lead to pneumonitis, which is characterized by shortness of breath, cough, fatigue, loss of appetite, and unintentional weight loss. Chronic pneumonitis can lead to scarring of the alveoli called pulmonary fibrosis resulting in permanent lung dysfunction. Regular exercise can condition the heart and lungs, increasing cardiovascular function and work capacity. This will allow a patient with pulmonary toxicity to maintain a higher level of function despite the loss of functional alveoli due to pulmonary fibrosis.
c. Hormonal Therapy
Existing research related to the effect of exercise on breast cancer patients receiving active hormonal therapy is sparse. Examining some limited data from a study done by Segal et al. suggests exercise may have a greater benefit to hormonal therapy patients in terms of aerobic capacity and body composition vs. that of their cohort receiving chemotherapy. Hormonal therapy patients are commonly known to exhibit side effects related to low estrogen, such as hot flashes and bone loss.
i. Hot Flashes
Preliminary research has emerged indicating that exercise is an effective treatment for hot flashes. While no direct cellular mechanism is yet fully understood, the physiology of a hot flash has been linked to the activation of the sympathetic nervous system via an increase of brain norepinephrine levels. Physical activity is not shown to directly attenuate norepinephrine release, exercise actually has been shown to increase short term serum norepinephrine levels. Straznicky et al  observed weight loss achieved via regular aerobic activity and caloric restriction achieved a mean 23% decrease of norepinephrine release in subjects. This is supported by the favorable changes in body composition in women undergoing hormonal therapy as observed by Segal et al. in the previously cited study. Keeping these studies in mind, it can be hypothesized that regular exercise leading to weight loss and a reduction in norepinephrine release can indeed reduce the symptoms of hot flashes felt by breast cancer patients undergoing hormonal treatment.
ii. Bone Density
Bone remodeling involves an intricate balance between osteoclastic bone resorption and osteoblastic bone formation in order to maintain a bone mineral density (BMD) necessary for movement and response to stress. Local factors, such as receptor activator nuclear factor-kappa B ligand (RANKL), RANK receptor, and osteoprotegrin (OPG), present in the bone microenvironment are the primary modulators of bone resorption and formation. RANKL binds to the RANK receptor on osteoclasts, thus increasing their activation and overall bone resorption.  Conversely, OPG acts as an antagonist by binding to RANKL and preventing its activation of RANK receptors, effectively halting bone resorption. This coupling of bone processes is influenced by several systemic and local components including circulating estrogens, other sex hormones, parathyroid hormone, vitamin D and others.
Decreased bone mineral density, namely osteoporosis, is a common health concern for individuals receiving treatment for breast cancer. It has been suggested that several factors contribute to reductions in BMD in this population including: therapeutic corticosteroid use, primary ovarian failure, and lack of physical activity. Additionally, chemotherapeutic agents such as doxorubicin, cyclophosphamide, and methotrexate have been shown in animal studies to contribute to bone-wasting.[74, 75, 76]
Estrogen levels are positively correlated with BMD. Estrogens directly stimulate the action of OPG and inhibit production of RANKL. Additionally, estrogens promote the activity of local growth factors such as insulin-like growth factor-1 (IGF-1), transforming growth factor-β (TGF-β), type-1 pro-collagen, and bone morphogenetic protein, while inhibiting osteoclastic activity via nitric oxide, TGF-β, and inhibition of interleukin-6.  Due to the role of estrogen in promoting both BMD and increasing risk of breast cancer, BMD may be considered a marker of breast cancer risk.
Treatment of breast cancer with alkylating agents such as cyclophosphamide, methotrexate, and doxorubicin commonly contributes to ovarian failure. Patients with ovarian failure experience reductions in estradiol and follicle-stimulating hormone similar to post-menopausal women. These decreases in sex hormones are instrumental in rapid and significant bone loss seen in patients following chemotherapy-induced ovarian failure.
Previous research has demonstrated that both resistance and aerobic exercise are beneficial to the bone health of women pre- and post-menopause.[78, 79] Interestingly, few studies have investigated the utilization of exercise in improving BMD in individuals with breast cancer. In a study examining the effects of both aerobic and resistance exercise on BMD in patients with breast cancer receiving chemotherapy, Schwartz and colleagues  found that individuals receiving adjuvant therapy that exercise aerobically 15-30 minutes per day at a moderate, symptom-limited intensity, and primarily weight-bearing manner maintained their BMD over the 6 month intervention period (decrease of 0.76%). In comparison, individuals performing resistance exercise (8-10 repetitions with thera-band, major muscle groups) and normal leisure activities experienced reduced BMD of 4.92% and 6.23%, respectively. Likewise, Irwin and colleagues  utilized a 30 minute per day (60-80% max heart rate), 6-month aerobic exercise program for breast cancer patients 6 months post-chemotherapy, and found favorable outcomes in BMD at 6 months, and significant improvements relative to usual care patients at 12 months (0.2% increase for exercise group, 1.7% decrease in usual care, p<0.05). Maintenance of BMD was noted in patients in the exercise group taking aromatase inhibitors—a significant finding due to the medication’s role in inhibiting the role of estrogen in RANKL-OPG balance.
One study has investigated the effectiveness of bisphosphonate therapy (IV zoledronic acid, 4 grams every 3 months for 15 months) compared to physical activity in the maintenance of BMD in breast cancer patients undergoing chemotherapy. Individuals in the physical activity group were given activity counseling by a physical therapist and a pedometer with guidelines to accumulate 10,000 steps per day. At 12 months, Bisphosphonate group members were shown to maintain their BMD significantly greater than the physical activity group at all measured sites, with the largest difference being in the lumbar spine (1.64% increase for Bisphosphonate, 6.12% decrease in physical activity group). Further research is necessary to propose specific exercise recommendations for the purpose of maintaining BMD in breast cancer patients.
d. Exercise Prescription Recommendations for Adjuvant Therapy
While the cellular mechanisms behind the side effects related to adjuvant breast cancer treatment are varied, several common themes emerge upon examination. First, general cardiovascular deconditioning occurs via both direct (damage to healthy tissues) and indirect (inactivity) effects of various treatments. Secondly, a proinflammatory response as a result of cytokine release can cause fatigue during adjuvant treatments. Lastly, estrogen deficiencies created in hormonal treatments (some as a response to radiation side effects) can lead to bone loss and negative cardiovascular consequences. Moderate aerobic and resistive exercise within the ACSM guidelines appears to be the best approach for women undergoing active treatment. Positive responses were seen across studies with aerobic protocols in the 60-80% MHR range, done 3-5 days a week.     They elicited positive pulmonary adaptations, attenuated proinflammatory cytokine release, maintained BMD, increased cardiac function, and improved quality of life measures.
Emerging research could potentially further support moderate aerobic activity as it has been noted to elicit cardioprotective benefits in estrogen depleted female rats. In this study female rats with low estrogen undergoing a single one hour bout of moderate exercise (75% max) showed an increased expression of Heat Shock Protein 70 (Hsp70).  Hsp70 was shown to preserve cardiac function in terms of left ventricle developed pressure, left ventricle end-diastolic pressure, and maximal rates of contraction and relaxation.. This could directly address the cardiac losses seen by Dong et al. in GnRHa therapy. These results should be interpreted with caution however due its applicability to humans being unknown at this time.
Intense exercise during adjuvant treatment is not recommended, the reasons for which are covered in the following section.
6. Potential Negative Effects of Exercise
Although moderate exercise has been shown to have a multitude of beneficial effects in patients with breast cancer, certain research studies have shown that too much exercise may have a negative effect.
Mammary tumors were chemically induced in female Sprague-Dawley rats through DMBA exposure. In a randomized controlled trial, 45 rats were divided into 3 groups: a control group, an exercise group, and an exercise group that was injected with melatonin. Exercise stress was provoked through forced swimming for 30 minutes, 5 days/week. Control rats were repeatedly immersed in the same water and handled for 30 minutes daily. No significant changes were found between groups in terms of survival time, though there was a trend for exercised rats to die more quickly. Exercise also did not change tumor multiplicity. However, the tumor growth rate was significantly increased in the exercising rats without melatonin. Exercising rats that were given melatonin demonstrated similar tumor growth rates as the controls—that is, melatonin counteracted the increased tumor growth induced by exercise. Rats with tumors had fewer NK cells and more prolactin and adrenaline versus rats without tumors. NK cell levels did not change with exercise or melatonin supplementation, but the highest levels of prolactin and adrenaline were seen in exercising rats without melatonin. Prolactin is a known breast cancer promoter in humans and this research demonstrates that intense levels of exercise cause prolactin levels to rise. Catecholamines such as adrenaline have also been shown to promote tumor growth, which was also reflected in the results of this study.
In a follow-up study, the effect of melatonin on catecholamine and prolactin in exercising rats was more closely examined. Melatonin may be therapeutic in breast cancer through anti-oxidant effects  and anti-stress mechanisms , regulating tumor growth through interaction with prolactin and catecholamine levels that are increased by stress. This new study additionally showed that melatonin can counteract prolactin and catecholamines specifically induced by exercise stress.
Together, the results of this research indicate that intense exercise may cause an increase in prolactin and adrenaline that, in turn, may lead to increased tumor growth. While these effects may be moderated by melatonin, clear cut protocols for humans have not been established. Therefore, as the exact exercise intensity threshold for enhancement of tumor growth has not been determined in humans, breast cancer patients should be strongly encouraged to follow the presented exercise guidelines until further research emerges in order to avoid any potential negative effects with excessive exercise.
The following is a summary of the research found on the effects of exercise at the cellular level in breast cancer patients, and recommendations based on individual cellular responses:
- It is recommended, based on the available literature, that an exercise program consisting of moderate intensity, interval walking at 40 and 70% aerobic capacity for at least 26 minutes daily is sufficient to limit aberrant methylation of genes indicated in carcinogenesis in healthy individuals. [11, 12, 15]
- Based on current literature, recommended physical activity to see the benefits of decreased estrogen, insulin and IGF-1 as well as increased SHBG is an exercise program of moderate aerobic activity at 70-80% HRR for 150-225 minutes a week. [16, 23]
- The effects of exercise on cytokines is continually being studied and right now there is not much evidence to support or refute the benefits of exercise on CRF and other factors influenced by cytokine levels. Based on beneficial effects of exercise found in the study by Sprod LK et al., the suggested recommendation for breast cancer survivors are to perform a moderately intense (RPE 3-5 on 1-10 scale) cardiovascular work out (i.e. walking) most days of the week. In addition, perform low to moderately intense resistance training most days of the week, with goal of 4 sets of 15 reps.
- Moderate intensity running for at least 3 miles per day has been shown in Dawley rats reduce mammary tumor size by limiting blood vessel density through reduction in VEGF, interrupt the G1/S transition of the cell cycle, and by initiating intrinsic apoptosis.  Additional rat models, injected with leukemia, demonstrated decreased tumor size compared to controls following an exercise program of 1 hour swimming sessions, for 5 days a week, over a 10 week period by inducing oxidative stress and lipid peroxidation.  In this study it was hypothesized that downstream dissociation between I-κB and NF-κB is indicative of attenuation of the cell growth cycle. 
- Moderate aerobic exercise performed at 60-80% of MHR, 3-5 times a week, appears to be the most strongly supported intervention for patients undergoing adjuvant therapies for breast cancer. Benefits have been seen in terms of reduced fatigue, maintenance of BMD, increased cardiopulmonary function, maintenance of bodyweight/composition, and improved quality of life.
The proposed exercise prescription based on the above findings is: Aerobic (~30 total minutes) and resistance training (4 sets of 15 reps) at low to moderate intensities (40-70% of VO2max) at least 3-5 days a week. Synthesizing all of the current research to produce specific recommendations for exercise parameters based off cellular mechanisms and responses leads to recommendation concurrent with current ACSM guidelines (listed in a table in the introduction sections). While it is possible negative effects may be seen with exercise, it is with only high intensities and, to date, has only been demonstrated in rats. Low to moderately intense exercise in breast cancer patients and survivors is not reported as harmful on a cellular level.