Scientists have long believed that obese women who develop a form of breast cancer fueled by the female hormone estrogen are more likely to die from the disease than lean women with the same diagnosis.
But, until now, they lacked a scientific explanation to support their theory.
A new study by scientists at MD Anderson Cancer Center explains in step-by-step detail the breast cancer-promoting impact of obesity. Their findings were published recently in the journal of the National Cancer Institute, with Enrique Fuentes-Mattei, Ph.D., a postdoctoral fellow in Molecular and Cellular Oncology, serving as lead author.
To arrive at their results, the researchers studied 137 patients with ER+ breast cancer — the type that proliferates in the presence of estrogen — before the patients received treatment, which allowed them to study how tumors begin and grow. Roughly 75% of breast cancer cases are ER+. The researchers also induced obesity in mice to observe breast cancer development in an animal model and compare it to human breast cancer development.
“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 Mong-Hong Lee, Ph.D., professor in Molecular and Cellular Oncology and 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 scientists pinpointed 59 “cancer hallmarks” — biological changes in normal cells that can lead to malignancy when obesity is present.
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.”
Sai-Ching Jim Yeung, M.D., Ph.D., professor in Emergency Medicine and director of the project, said the study has “set the ground” for 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 Epidemiology, and Vicente Valero, M.D., chair ad interim 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).