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Metabolic Syndrome and Breast Cancer Models

By Negin Martin
April 2009

La Merrill, Michele
La Merrill is currently a postdoctoral fellow in community and preventive medicine at the Mount Sinai Medical Center. She received the Best Manuscript Award from the Occupational and Public Health Specialty Section at this year's Society of Toxicology Annual Meeting - the latest of several she has won during her studies as a doctoral student and postdoctoral fellow. (Photo courtesy of Michele La Merrill)

In a new study, funded in part by NIEHS, a collaborative research team reports data supporting the hypothesis that distinct mouse models of breast cancer respond differently to high fat diet and exposure to the endocrine disruptor dioxin and manifest different phenotypes of metabolic syndrome. Their findings were published in the American Journal of Physiology - Endocrinology and Metabolism. The authors conclude that their findings "may have utility in elucidating the mechanisms of those metabolic syndrome-associated phenotypes that are etiologically linked to breast cancer risk."

The team included lead author Michele La Merrill, Ph.D., Principal Investigator David Threadgill, Ph.D., of the University of North Carolina Chapel Hill (UNC), NIEHS Director Linda Birnbaum, Ph.D., and colleagues from the Environmental Protection Agency (EPA), UNC and University of California, Davis (UCD).

The study ( investigated the effects of high fat diet and dioxin exposure in litters of three different mouse breast cancer models - HER2, PyMT, and DMBA. These mice have a uniform genetic background with the exception of specific oncogenes or exposures to carcinogen that make them more prone to developing breast cancer. The mouse models used in this cross-model comparison represent three different subtypes of human breast cancer. Women with these different types of breast cancer could react similarly to environmental factors such as dioxin and high-fat diets.

The team dosed pregnant mice with low levels of dioxin and placed the pups on a high- or low- fat diet after birth. Researchers measured weight, percent body fat and blood glucose levels of pups throughout the study. Triglyceride levels were measured at the end of the study.

Breast cancer model mice raised on HFD had earlier pubertal growth spurts. Body fat and adipose tissue accumulated faster in the HER2 model after puberty as compared to DMBA and PyMT mice. DMBA mice had higher glucose levels than the other two. Dioxin influenced the triglyceride levels only in the PyMT mice that were fed HFD. These data are the first to show that mouse breast cancer models manifest different phenotypes of metabolic syndrome even before developing cancer.

Despite shared risk factors, the association between developing metabolic syndrome and breast cancer has not been well studied. Breast cancer in humans can be categorized into several subtypes depending on such factors as genetic background, prognosis and response to different treatments. Prior to this study, the ways each breast cancer type could predispose an individual to developing metabolic syndrome when exposed to environmental toxins and high-fat diets remained unclear.

Metabolic syndrome is a combination of risk factors, such as obesity, high levels of blood glucose and overproduction of insulin, that make an individual susceptible to developing cardiovascular disease or diabetes. According to the study, statistical analysis of the third National Health and Nutrition Examination Survey (NHANES) indicates that more than 47 million US residents are affected by diseases stemming from metabolic syndrome - with the number expected to increase in the future. In addition, the prognosis for people with metabolic syndrome worsens with advanced age, high-fat diet and a sedentary lifestyle.

Metabolic syndrome and breast cancer share several common risk factors. For example, obesity - a component of metabolic syndrome - can cause insulin insensitivity, type 2 diabetes and hormonal imbalance. Scientific evidence supports an association between type 2 diabetes, obesity, hormonal disruption and high risk of breast cancer among postmenopausal women. Another component of metabolic syndrome - accumulation of adipose tissue - results in storage of fatty acids and triglycerides and causes estrogen aromatization that also increases the chances of breast cancer.

Typically, individuals with metabolic syndrome or obesity consume more fatty food from animals, which raises their dioxin intake. Dioxin disrupts endocrine signaling, and chronic low-dose exposure promotes diseases such as type 2 diabetes and breast cancer. The resulting excess adipose tissue slows clearance of dioxin and increases susceptibility to the toxin.

(Negin Martin, Ph.D., is a research fellow in the NIEHS Membrane Signaling Group. She was recently chosen as a 2009 Science Communication Fellow with Environmental Health Sciences.)

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