High Levels of Leptin May Contribute to Breast Cancer Risk

SAN FRANCISCO—Increased circulating levels of the protein leptin, whichregulates body fat and fat mass, may be a risk factor for postmenopausal breastcancer, according to a presentation at the 93rd Annual Meeting of the AmericanAssociation for Cancer Research (abstract 2503).

"These results clarify why women who are overweight are at greater risk for breast cancer after menopause," said Margot P. Cleary, PhD, associate professor, the Hormel Institute, University of Minnesota, Austin.

Leptin levels are known to increase in concert with increases in body weight and mass. In previous experiments, scientists found that leptin is expressed in mammary tissues and in some breast-cancer-derived cell lines. However, the functional role of leptin in breast cancer progression is unknown, and leptin receptors have not been identified in normal or cancerous mammary tissues.

Previous studies, however, have shown leptin receptors to be present in lung, adrenal, stomach, and intestinal cancers, Dr. Cleary said.

To help elucidate leptin’s role in obesity and breast cancer, Dr. Cleary and her colleagues did a series of in vivo and in vitro studies. They first identified an active form of the leptin receptor that is present in both normal and cancerous cells. The long form of the leptin receptor OB-Rb is expressed in the HBL100 normal breast cell line and in the transformed estrogen-responsive breast cancer cell line T-47D, they found.

When leptin was added to a medium in which normal HBL100 cells and T-47D breast cancer cells were growing, both kinds of cells experienced enhanced rates of growth. After 10 days in the presence of leptin, cell number was enhanced in HBL100 cells by 56% and in T-47D cells by 160%, compared with controls that were not stimulated with the fat-regulating protein.

When leptin was added to both normal and breast cancer cells, the scientists noted the phosphorylation of downstream signaling proteins STAT3 and ERK in both types of cell lines.

While leptin did not appear to enhance anchorage-independent colony formation in the HBL100 normal cells, T-47D cancerous cell lines experienced a 100% increase in colony formation in response to leptin. Thus, in the presence of higher leptin levels, the T-47D cells might have an increased capacity to develop tumors.

Murine Studies

The researchers also looked at the effect of leptin on tumor incidence in mice that contain the human protein MMTV-TGF-alpha, which confers a 50% risk of developing mammary tumors.

Mice with MMTV-TGF-alpha that had been crossbred with mice that either lack circulating leptin or lack functioning leptin receptors developed no mammary tumors. In their wild-type counterparts with MMTV-TGF-alpha, however, there was a 50% incidence of mammary tumor development, as expected, she said.

"This mouse model indicates that mammary tumors don’t develop in the absence of leptin or a leptin receptor," Dr. Cleary said. "Our results suggest that if a woman gains weight around the time of menopause, the increase in leptin levels could enhance the proliferation of cells that have the potential to develop into breast cancer."

This research adds to previous studies that have shown that high estrogen and insulin levels and weight gain increase breast cancer risk in postmenopausal women. Taken together, such recent research substantiates the necessity for public health advocates to continue to urge people to lose weight if they are obese, she said.

In a later interview, Dr. Cleary also pointed out that regardless of the age of onset, obesity at the time of breast cancer diagnosis worsens a woman’s prognosis in terms of survival and recurrence. Thus, even for premenopausal women, higher leptin levels may be dangerous.

Leptin does have a positive role, Dr. Cleary noted. Other clinical studies have shown that leptin is important in reproduction and bone growth. But while it may be important in bone formation, it may not play a role in bone maintenance in the menopausal years, she said.

Further research should establish what level of leptin affects breast cancer risk, Dr. Cleary said. "It may be that if you stay within a certain normal limit, leptin is not a problem," she said. "But beyond a certain high level, it may be associated with weight gain."

Future Drug Development

The best way now to prevent high leptin levels is to stay at a normal weight or to lose pounds if one is obese. But in the future, there may be drugs developed that could interfere with leptin’s effect in the body, she said.

"This would probably be a medication that would interfere with leptin binding. But that is far in the future," Dr. Cleary said. "Right now, we are simply providing an explanation for why obesity is a risk factor for postmenopausal breast cancer."