Systemic changes occurring during exercise can reduce breast cancer cell viability and decrease tumorigenesis through regulation of the Hippo signaling pathway.  [Melanie Taylor/Getty]
Systemic changes occurring during exercise can reduce breast cancer cell viability and decrease tumorigenesis through regulation of the Hippo signaling pathway. [Melanie Taylor/Getty]

There is substantial epidemiological evidence to suggest that exercise can protect against breast cancer risk, and also help to reduce the likelihood that breast cancer will recur in treated patients. What scientists don’t yet understand is how exercise helps to reduce the risk of breast cancer recurrence, and there has been limited prior research on the mechanisms that might underpin these beneficial effects.

Researchers in Denmark now report that elevated levels of epinephrine in the blood of breast cancer patients after just one session of exercise activate stops breast cancer cells from growing in vitro, and also prevents the cells from developing into tumors in experimental mice. The antitumor effects appear to be related to activity of a relatively recently identified tumor suppressor signaling pathway. “I’m surprised at how strong the effect of exercise and epinephrine was on tumor formation and metastasis,” commented Pernille Hojman, Ph.D., who led the studies at the University of Copenhagen’s Centre of Inflammation and Metabolism and Centre for Physical Activity Research, to GEN.

Dr. Hojman’s team reports its findings in Cancer Research, in a paper titled “Exercise-induced Catecholamines Activate the Hippo Tumor Suppressor Pathway to Reduce Risks of Breast Cancer Development.”

Prior studies have suggested that long-term reductions in circulatory risk factors, such as sex hormones, metabolic hormones, and low-grade inflammation might link exercise-related weight loss with breast cancer risk reduction. Previous work by Dr Hojman’s group indicated that, in contrast with long-term adaptations in breast cancer risk factors, the benefits of exercise may be more acute, and changes in circulating factors after just one session of exercise could reduce breast cancer cell viability by 10%. “Last year, we published a study showing that voluntary wheel running in mice decreased tumor growth across a number of tumor models,” Dr. Hojman explained. ‘In that study, we identified the mechanisms behind this protection as an epinephrine-driven mobilization of cytotoxic immune cells, which then were redistributed to the tumors.”

Building on this work, the researchers have now looked more closely at factors in post-exercise serum that might impact on breast cancer cell survival. Given the importance of epinephrine in the previous study study, “we continued to evaluated if epinephrine also has a direct affect on tumor growth and metastasis, as identified in the current study,” Dr Hojman noted.

The team first incubated breast cancer cells from cancer cell lines in serum collected from breast cancer patients and from healthy women, both before and after the subjects undertook a controlled, 2 hour session of moderate to intense exercise. All the breast cancer participants were undergoing adjuvant chemotherapy following stage I/II breast cancer surgery.

Two different breast cancer cell lines were used, the hormone receptor-positive MCF-7, and the triple negative cell line MDA-MB-231. Both were incubated for 48 hours in serum obtained from the women either before, or after exercise. What they found, was that compared with cells incubated in pre-exercise serum, the viability of MCF-7 cells incubated in the exercise-conditioned serum was reduced by 11%, and MDA-MB-231 cell viability was reduced by 9%.

Preincubation in exercise-conditioned serum also dramatically reduced the ability of MCF-7 cells to form tumors in experimental mice. Forty five percent of animals inoculated with exercise-induced serum MCF-7 cells developed tumors, compared with 90% of mice inoculated with control MCF-7 cells that had been incubated in serum taken before exercise. Tumor incidence in mice injected with MDA-MB-231 cells that had been preincubated with the exercise-conditioned serum was also lower than in the mice receiving the control serum-incubated MDA-MB-231 cells.

Analysis of the exercise-conditioned serum identified elevated levels of both epinephrine and norepinephrine, as well as increased levels of other known exercise-related factors, including serum lactate and IL6.  But when the researchers blocked beta-adrenergic signaling by adding the beta-blocker propranolol to the exercise-conditioned serum, the suppressive effects of this serum on MCF-7 cell viability (although not MDA-MB-231 cells) was significantly reduced, and the cells were more able to form tumors in experimental mice.

“Only half of the mice injected with hormone sensitive breast cancer cells developed small tumors after these cells had been incubated with patient serum taken immediately after an exercise training session,” Dr. Hojman reiterates to GEN. “And this effect was lost if we blocked adrenergic signaling. In contrast, almost all the mice developed tumor after incubation with patient serum taken at rest. That indicates that the effect of exercise and epinephrine is much stronger on the metastatic process than on direct tumor growth control.”

Further analysis confirmed that the effects of exercise-induced epinephrine and norepinephrine on MCF-7 cell viability and tumor-forming potential were mediated through the Hippo tumor suppressor signalling pathway, which is known to be dysregulated in a number of cancers, including breast cancer, the authors note. They found that the elevated levels of epinephrine in post-exercise serum activated the Hippo pathway in the MCF-7 cells, but not in the MDA-MB-231 cells.

Dr. Hojman suggests that there are epidemiological data indicating that exercise might be better at reducing the risk of recurrence of hormone receptor-positive breast cancer than of triple-negative breast cancer, which might explain why the effects of serum obtained after exercise were more pronounced on MCF-7 cells. “Hippo signaling is involved in basal organ development, thus this pathway controls the formation of tumors,” she states to GEN. “It is still a fairly newly identified pathway, thus we are just starting to understand the implications of its activation and deactivation.”

In a final set of experiments, the researchers evaluated the effects of exercise on breast cancer tumor growth in female mice that received injections of either MCF-7 or MDA-MB-231 tumor cells, and were housed in cages either with or without running wheels. Mice with access to running wheels ran voluntarily for approximately 4 km per night, and among these mice there was a 36% reduction in growth of the MCF-7 tumors, and a 66% reduction in MDA-MB-231 tumor growth, when compared with tumors in control mice that had no access to running wheels.

“The current study is the first to demonstrate that systemic changes occurring during exercise can reduce breast cancer cell viability and decrease tumorigenesis through regulation of the Hippo signaling pathway,” the authors write.  “Taken together, our findings offer a mechanistic explanation for exercise-dependent suppression of breast cancer cell growth.”

The key takeaway message from the study is that exercise can have an effect on tumor cell growth and the metastasis process, Dr. Hojman tells GEN. “Yet this regulation is dependent of increases in epinephrine. This can be obtain if the performed exercise is of moderate to high intensity and associated with increases in heart rate and heavy breathing. But if this is attained, then the exercise only needs to be of short duration (e.g., 15 minutes). In our study, we found that breast cancer patients in adjuvant chemotherapy were indeed capable of performing the required exercise, so it is feasible for cancer patients to do the exercise training.”

In Denmark all cancer patients who have completed primary therapy for cancer are entitled to 3 months of active rehabilitation, including supervising exercise training, she continued. “Thus good physical rehabilitation programs are already established in the municipality setting for cancer survivors. On the research part, we are working with exercise interventions during the pre-operative phase. In this fall, we are planning to start a randomized controlled exercise intervention study in patients with upper GI cancer during their 12 weeks of neoadjuvant chemotherapy. Here the aims are to study the effect of exercise training on risk of postoperative complications, as well as tumor specific regulation of the Hippo signaling, as identified in this paper, and other intratumoral signaling pathways involved in tumor control.”

 *Article updated September 8, 2017 to include comments by study author.

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