3D image of breast cancer metastasizing representing HER2 breast cancer.
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Obesity may spur DNA damage in the breast tissue of women who carry BRCA1 or BRCA2 mutations, possibly contributing to breast cancer development in this already high-risk group, according to new research led by Weill Cornell Medicine scientists.

“Our research provides clinicians with mechanistic evidence of the possible benefits of intervening on the metabolic side of the breast cancer disease process,” said senior study author Kristy A. Brown, the Emilie Lippmann and Janice Jacobs McCarthy Research Scholar in Breast Cancer at Weill Cornell Medicine.

The study, published in a recent issue of Science Translational Medicine, suggests that weight management and medications that impact metabolic health may be an important part of preventive care for women with these genetic mutations.

It is estimated that 5 to 10% of breast cancers are inherited. BRCA1 and BRCA2 are two genes that play a role in this disease. Mutations in these genes are the leading cause of hereditary breast cancer.

Obesity (defined as a body mass index [BMI] ≥ 30) and poor metabolic health are also known breast cancer risk factors, “but whether these modifiable risk factors contribute to breast cancer development in BRCA mutation carriers has been largely unknown,” said Brown.

Prior findings from epidemiological studies of the impact of body weight on breast cancer development in BRCA mutation carriers are unclear, according to the paper’s first author Priya Bhardwaj, a doctoral candidate in the Weill Cornell Graduate School of Medical Sciences when the current research was being conducted

These researchers analyzed noncancerous breast tissue samples from patients with either BRCA1 or BRCA2 mutations who had undergone mastectomy. The study population included women who had a BMI  in the lower range of below 25 kg/m2 and those with a BMI of 25 or higher, categorized as overweight or obese.

Using immunofluorescence, the team found that higher BMI in women with BRCA mutations was positively correlated with DNA damage in the milk glands. They also determined that the metabolic hormones leptin and insulin, and the hormone estrogen, which is commonly linked with breast cancer growth, were drivers of this DNA damage.

Furthermore, the scientists found that they could reduce DNA damage in tissue samples in the lab by exposing them to metformin. This drug, commonly used to manage type 2 diabetes, is also known to suppress the expression of aromatase—an enzyme that is responsible for estrogen biosynthesis.

“Metformin is an attractive option to study because it has very limited side effects, and we can think about the possibility of using it in a risk reduction setting,” Brown said. “However, we still need to determine which biomarkers can be used as clear indications of risk reduction in this patient population, beyond closely following people for cancer development.”

In addition to their tissue studies, the researchers assessed mice with BRCA1 mutations to better understand whether an increase in DNA damage is associated with cancerous tumor growth. They found that obese mice with metabolic dysfunction had higher rates of tumor formation than lean mice.

“Not only did obese mice develop tumors earlier, but they also developed tumors at a higher incidence overall by the end of the study,” Bhardwaj said.

The researchers plan to further study the mechanisms that drive DNA damage in the breast tissue of women with BRCA mutations and hope to encourage the clinical study of lifestyle changes or metformin in these patients.

“This line of research may go beyond BRCA1 and BRCA2 mutation carriers,” Brown said. “It may also have an impact on other hereditary cancers or cancer types.”

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