• Posted February 27, 2023

Is Obesity Especially Dangerous for Women at Genetic Risk for Breast Cancer?

Certain gene mutations put women at high risk of breast cancer, and now an early study hints that obesity might make matters worse.

The findings come from a study of breast tissue samples from women who carried particular mutations in genes called BRCA1 and BRCA2 -- which convey much higher-than-normal risks of both breast and ovarian cancers.

The researchers found that among women who were obese, healthy breast tissue showed more signs of DNA damage that can promote cancer.

The findings, published Feb. 22 in the journal Science Translational Medicine, do not prove that obesity exacerbates the already high breast cancer risk in women who carry BRCA mutations.

But they do raise that possibility, according to senior researcher Kristy Brown, an associate professor at Weill Cornell Medical College, in New York City.

If so, that would mean that maintaining a healthy weight might mitigate some of the cancer risk that BRCA mutation carriers face.

Brown's team also found hints of another potential avenue: In lab experiments with carriers' breast tissue samples, they found that exposing the tissue to the diabetes drug metformin reduced signs of DNA damage.

"We definitely need more studies to see whether lifestyle interventions, or metformin, can lower the risk of cancer in these patients," Brown said.

BRCA gene mutations are not common: In the United States, about 1 in 500 women carry a mutation in either BRCA gene, according to the U.S. Centers for Disease Control and Prevention.

But when they occur, they have a substantial impact. About half of women with BRCA mutations develop breast cancer by age 70, while 30% develop ovarian cancer, according to the CDC. That compares with 7% and 1%, respectively, among U.S. women as a whole.

Faced with those odds, many women with BRCA mutations opt for risk-reducing surgery to remove their breasts, ovaries or both. Others use medications to block the actions of estrogen in the body.

As for lifestyle measures, the picture is less clear. Obesity, and being sedentary, are considered risk factors for postmenopausal breast cancer among women at average risk.

But population studies -- where people are asked about their weight -- have not been able to pin down whether obesity contributes to cancer in women with BRCA mutations, according to Brown.

"So, we took a different approach with this study," she said.

Her team analyzed healthy breast tissue from 69 women with BRCA mutations who underwent mastectomies as a preventive measure. The investigators found that tissue from obese women generally showed more signs of DNA damage that can precede the development of cancer, versus leaner women.

Then, in experiments with lab mice with BRCA mutations, the researchers found that greater amounts of body fat correlated with more DNA damage in breast tissue and greater growth of breast tumors.

Obesity has an array of effects in the body, including raising levels of estrogen and insulin -- a hormone that regulates blood sugar. And Brown's team found clues that those hormones may be factors in the DNA damage seen in BRCA carriers with obesity.

For one, they found that treating women's breast tissue samples with an estrogen-blocking medication reduced DNA damage in the cells.

The researchers then had similar results when they treated the samples with metformin -- a widely used, inexpensive diabetes drug. The medication improves the way the body handles insulin, but it apparently has another effect, Brown said: It reduces estrogen in breast tissue, at least in the lab.

That last point is important, according to Brown and other experts, since the human body is much more complex than a lab dish.

"This study was done on tissue samples in a lab and animal models, not in people," said Susan Brown, senior director of health information and publications at the breast cancer nonprofit Susan G. Komen.

In general, she said, lifestyle measures are hard to study, and at this point "have shown limited benefit for those with a BRCA mutation."

Of course, no one would counsel a woman with the gene mutations against a healthy lifestyle, either.

Anyone can benefit their overall health by getting regular exercise, limiting alcohol and maintaining a healthy weight, she noted.

Dr. Julia Smith, an oncologist at NYU Langone's Perlmutter Cancer Center, in New York City, specializes in prevention for people at increased risk of developing cancer.

She called the study "interesting," but also "very preliminary."

"It cannot be used in and of itself to make treatment recommendations," Smith said.

She agreed, though, on the bigger picture.

"Lifestyle issues should be addressed in all patients, whether they are [BRCA] mutation carriers or not," Smith said. "That's important for the risk of numerous cancers and other medical diseases, as well."

More information

Susan G. Komen has more on BRCA mutations.

SOURCES: Kristy Brown, PhD, associate professor, biochemistry in medicine, Weill Cornell Medical College, New York City; Susan Brown, MS, RN, senior director, health information and publications, Susan G. Komen, Dallas; Julia Smith, MD, PhD, clinical assistant professor, medicine, NYU Grossman School of Medicine, medical oncologist, Perlmutter Cancer Center, NYU Langone Health, New York City; Science Translational Medicine, Feb. 22, 2023, online