Study points to higher risk of breast cancer progression in obese women

MD Anderson News Release 06/27/14

Scientists have long believed that obese women who developed estrogen-positive (ER+) breast cancer were at higher risk for death from the illness than lean women with the same diagnosis. Close to 75 percent of all breast cancers are estrogen receptor-positive and will proliferate in response to the female hormone estrogen.

A new study comparing obese mice with breast cancer and biological changes in breast cancer samples from patients appears to indicate the tie between obesity and higher risk for death.  By analyzing biopsy samples from 137 ER+ breast cancer patients before they received treatment, and developing an “obese” transgenic mouse model to study how tumors begin and grow, scientists at The University of Texas MD Anderson Cancer Center were able to show evidence for how obesity may cause some women to develop ER+ breast cancer more quickly – and with more deadly results. 

“Obesity increases the risk of cancer death among postmenopausal women with ER+ breast cancer, but the direct evidence for how this occurs is lacking,” said Enrique Fuentes-Mattei, Ph.D., in the Department of Molecular and Cellular Oncology. 

Fuentes-Mattei was the lead author of an article about the study, featured in this week’s issue of the Journal of the National Cancer Institute.  Mong-Hong Lee, Ph.D., a professor in the same department and Sai-Ching Jim Yeung, M.D., Ph.D., a professor in the Cancer Center’s Department of  Emergency Medicine, were the senior authors for the article. 

The paper, “Effects of Obesity on Transcriptomic Changes and Cancer Hallmarks in Estrogen Receptor-Positive Breast Cancer,” revealed that obesity in these patients were associated with changes in 59 biological processes linked to  “cancer hallmarks” that allow one to distinguish normal cells from malignant cells.

“We examined the impact of fat cells and the proteins secreted by them on breast cancer growth in both human and mouse breast cancers,” said Lee, the principal investigator of the basic science component of the project. “Our study reported direct evidence about the breast cancer-promoting impact of obesity and the biological functions and cellular signaling mechanisms involved in patients and in the laboratory experimental models.”

The study showed that fat cell proteins known as adipokines change the gene expression profile in breast cancer cells, promoting tumor growth and proliferation. The scientists also found that the diabetes drug metformin and the targeted therapy drug everolimus, when given together, suppressed fat cell-induced tumor growth in the obese mice.

The transgenic obese mice had a “statistically faster risk for growing breast cancer and shorter overall survival rates” than mice with normal body weight. Both obese and lean mice were genetically predisposed to developing breast cancer. The authors concluded that adipokine secretion and a cellular “signaling” pathway known as the AKT/mTOR pathway play important roles in obesity-accelerated breast cancer development. Other contributors include excessive insulin levels, estrogen “signaling”, and inflammation, all secondary to obesity.

“Analysis of the interactions between estrogen, insulin and adipokines revealed a complex web of ‘cross-talk’,” said Lee. “We were able to observe that estrogen and fat hormone signaling play major roles in both humans and mice when it comes to tumor growth.  Our findings give a comprehensive overview as well as direct evidence for the mechanisms associated with obesity-induced poor clinical outcomes such as overall survival, progression-free survival, tumor-growth aggressiveness, and metastasis.”

Yeung, the director of the project, adds that the study has “set the ground” for better targeting some patients for treatment with metformin and everolimus as part of the therapeutic strategy.

“We believe that our mouse model will be a useful tool for future research on the development of therapeutic strategies that would block or reverse the effect of obesity on cancer,” said Yeung.

An MD Anderson clinical trial based on this study is currently in progress. It is led by 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.

The study was funded by the Susan G. Komen for the Cure Promise Grant (KG081048); the National Cancer Institute  at the National Institutes of Health (RO1-CA89266; a Cancer Center Support Grant (P30-CA16672) to MD Anderson; the Breast Cancer Research Foundation; and the National Institutes of Health Loan Repayment Program, Minority Supplement (3-R01CA089266-08S1, 3-RO1CA089266-09S1, and 3-RO1CA089266-10S1), and Training Grant Program in Molecular Genetics (T32-CA009299); the Vietnam Education Foundation; the Rosalie B. Hite Foundation; and the Department of Defense Breast Cancer Research Program (W81XWH-10-0171).