Nearly 1 million women worldwide are diagnosed with breast cancer on a yearly basis, with a large majority of them being postmenopausal. This tends to be the age when women gain significant body weight. After age and family history, obesity and its associated increase in estrogen levels seems to correlate with an increased incidence and higher risk of death from breast cancer in postmenopausal women.
While the International Agency for Research on Cancer and the World Cancer Research Fund have concluded that there is a convincing link between obesity-dependent breast cancer and the presence of estrogen receptor positive (ER+) tumor cells, the cellular factors or mechanisms that mediate this process have remained undiscovered. A recent study by a group of scientists and physicians at the University of Texas MD Anderson Cancer Center have found new clues to this connection.
Investigators noticed that based on medical records of 137 breast cancer patients, obesity and elevated estrogen levels correlated with reduced chances of survival. Analysis of gene expression patterns from tumor biopsies of these patients revealed changes in 59 different genes that affect biological processes with demonstrated roles in carcinogenesis. To gain further evidence of this relationship, they developed a transgenic mouse model that mimics the conditions in obese breast cancer patients, including high body fat, glucose intolerance, insulin resistance, and elevated estrogen. Like their human counterparts, these obese mice showed faster progression of breast cancer, larger tumors, and reduced survival compared to their lean littermates.
Comparison of gene expression profiles between humans and mice revealed a role for adipokines, secreted factors from fat cells, in accelerating obesity-dependent ER+ breast cancer. Secreted adipokines increased the growth of breast cancer cells in an in vitro setting. Metformin, commonly used in the treatment of diabetes, was shown to inhibit this effect by reducing the production of several adipokines, while specifically increasing that of adiponectin. This study also identified a role for the AKT/mTor cellular signaling pathway in accelerating breast cancer progression in obese mice and humans. The investigators used in vivo bioluminescent imaging of tumors, a technique that allows real-time visualization of tumor cell growth and spread, when injected in mice. Breast cancer cells injected into obese mice grew faster, and formed larger tumors than in lean mice. Treatment of obese mice with metformin or everolimus, both of which inhibit AKT/mTOR, reduced the tumor growth and the expression of downstream members of this signaling pathway.
“Our findings give a comprehensive overview as well as direct evidence for the mechanisms associated with obesity-induced poor clinical outcomes” writes Enrique Fuentes-Mattei, Ph.D., the lead author for the study and a member of the Department of Molecular and Cellular Oncology at the University of Texas MD Anderson Cancer Center. Mong-Hong Lee, Ph.D., and Sai-Ching Jim Yeung, M.D., Ph.D., senior authors for the publication are confident that this study will allow better targeted treatment of ER+ breast cancer patients using metformin and everolimus. This newly developed mouse model will also serve as a powerful tool for further investigations into the connection between obesity and cancer.
A clinical trial on the basis of these finding is currently in progress at MD Anderson, under the guidance of Francisco Esteva, M.D., Ph.D., adjunct professor in the Department of Epidemiology, and Vicente Valero, M.D, chair ad interim of the Department of Breast Medical Oncology.
This study was published in the Journal of the National Cancer Institute and received funding from the Susan G. Komen Foundation; the National Institutes of Health; the Breast Cancer Research Foundation; the Vietnam Education Foundation; the Rosalie B. Hite Foundation; and the Department of Defense Breast Cancer Research Program.