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Obesity Linked to DNA Damage, Breast Cancer Risk in Women Harboring BRCA Mutations

NEW YORK — Obese women with BRCA1 and BRCA2 mutations could be at higher risk for developing breast cancer compared to women who harbor the same mutations but have normal body mass index (BMI), new research suggests.

A team led by researchers from Weill Cornell Medicine found a positive correlation between high BMI (greater than 30) and DNA damage in breast epithelia of women with BRCA1 and BRCA2 mutations. Breaks in DNA can lead to breast cancer, the authors noted.

"We know that in the general population, obesity and metabolic dysfunction are associated with an increased risk of developing breast cancer. But this was less clear in women with BRCA mutations who are already at high risk," said corresponding author Kristy Brown, associate professor of biochemistry in medicine at Weill Cornell Medicine.

For their study, published in Science Translational Medicine on Wednesday, Brown and colleagues studied breast tissues of 69 women with BRCA mutations and BMIs ranging from 19.38 to 44.9 kg/m², who had undergone mastectomies. Immunofluorescence staining studies showed that higher BMI was correlated to more DNA damage.

Next, using RNA sequencing, they found changes in the breast adipose microenvironment of the obese women with BRCA mutations, including increased estrogen production. They also discovered that, in breast tissue explants cultured from women with BRCA mutations, blocking estrogen synthesis or receptor activity reduced DNA damage.

Brown said more studies are needed to understand if estrogen blockage can be used as a target to reduce the risk of developing breast cancer.

"The identification of pathways related to estrogen biosynthesis (tissue) and signaling (epithelial cells) was of particular interest given the availability of clinically approved drugs that target estrogen," the authors noted.

Meanwhile, the researchers also found that obese women with BRCA mutations had elevated levels of insulin and leptin in their breast tissues. Metformin, a drug used to treat type 2 diabetes, was found to be effective at reducing breast epithelial cell DNA damage, subsequent experiments showed.

"Reducing weight, for example, and improving metabolic health has been shown to be protective against the development of various cancers, including breast cancer in postmenopausal women. It will be interesting to see if these lifestyle interventions can also reduce the risk of breast cancer in women who carry a BRCA1 or a BRCA2 mutations," Brown said. 

Brown highlighted that one of the major limitations of the study was a small sample size. Studying more cases "would have helped better to tease out the effects of the specific BRCA mutations and could help look at the impact of menopausal status, which may not necessarily be possible based on 69 cases only," she said.