Scientific Exploration of Obesity and Breast Cancer Link

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Investigators at Memorial Sloan Kettering Cancer Center, Weill Cornell Medical Center, Rockefeller University, and the National Cancer Institute are moving forward in their understanding of the adverse association between obesity and breast cancer. Preliminary studies show associations between adipocytes, aromatase, proinflammatory cytokines, low-grade chronic inflammation, and breast tumors. Improved understanding of these associations will hopefully lead to targeted interventions.

Why the focus on obesity and breast cancer? Obesity is projected to affect more than 60% of the population in the United States by the year 2030. This will have widespread consequences for many diseases, said Clifford Hudis, MD, chief of the Breast Cancer Medicine Service at Memorial Sloan Kettering Cancer Center, New York City, and immediate past president of ASCO.

“The unprecedented change in rates of obesity has broad public health implications. What does this have to do with cancer? Uterine cancer mortality is higher in obese people, and cancers of the esophagus, pancreas, breast, and liver are associated with obesity,” he explained.

Further, obesity is a risk factor for postmenopausal breast cancer (but not for premenopausal breast cancer). “Explanations for this association are both facile and complex,” Hudis continued.

“We all know that adipocytes make estrogen, but the answer as to why this happens is complex and involves insulin and insulin-like growth factor. A new discovery is that adipocytes produce inflammatory macrophages that alter interleukin (IL)-6, IL-1, and tumor necrosis factor-alpha,” Hudis explained.

“We began to develop the notion that at least part of this was due to increased inflammation. Postmenopausal breast cancer may be a consequence of chronic low-grade inflammation in visceral fat and breast tissue,” he said.

Studies in mice showed the highest aromatase levels in oophorectomized animals in white adipose tissue in the mammary gland and visceral fat. Animals on a eucaloric diet seemed to put on a few pounds during menopause induced by oophorectomy.

“An unexpected finding we stumbled on were crown-like structures [CLS] consisting of dead or dying adipocytes in the animals, surrounded by macrophages that secrete proinflammatory mediators. This is a toxic stew of inflammation in the mammary gland of the mouse. Higher amounts of fat in oophorectomized animals contribute to the rates of CLS,” he explained.

The investigators went on to look at this in normal tissue in women’s breasts in patients undergoing surgery. In an initial series of 30 patients, they encountered parallel findings to what they saw in mice, including histological evidence of CLS of the breast white adipose tissue associated with increasing body mass index.

Hudis pointed out that a small number of obese and overweight patients do not have evidence of low-grade chronic inflammation, and that a modest number of overweight and even lean patients demonstrate elevated proinflammatory mediators and CLS of the breast.

“We have confirmed the pattern seen in mice in women’s breasts,” he emphasized. “We think this is a systemic phenomenon, and the white adipose tissue of the breast can be a sentinel for generalized inflammation,” Hudis said.

The current goal of studies is to define biomarkers that identify adipocyte inflammation with the potential to modulate and target it.

“We think this axis of obesity-inflammation-aromatase may be useful for reducing the risk of breast cancer or its progression. It may be a biomarker, and we need to scientifically investigate the effect of lifestyle changes and anti-inflammatory agents on these lesions,” he said. “We think that obesity may replace cigarette smoking as the nation’s number 1 risk factor for cancer.”

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