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 multi-institutional translational research.

The study, published in 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, although further research is needed.

Obesity and poor metabolic health are known breast cancer risk factors in the general population, “but whether these modifiable risk factors contribute to breast cancer development in BRCA mutation carriers has been largely unknown,” said senior study author.

Prior findings from epidemiological studies of the impact of body weight on breast cancer development in BRCA mutation carriers are unclear, said the paper’s first author. “Our research provides clinicians with mechanistic evidence of the possible benefits of intervening on the metabolic side of the breast cancer disease process,” she said.

The 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 body mass index (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 researchers found that higher BMI in women with BRCA mutations was positively correlated with DNA damage in the milk glands. They 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,” the senior author 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. The scientists 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,” the first author said.

Overall, this study contributes to a better appreciation of the effects of lifestyle, obesity and metabolic health on cancer development in high-risk populations, the senior author 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,” the senior author said. “It may also have an impact on other hereditary cancers or cancer types.”

https://www.science.org/doi/10.1126/scitranslmed.ade1857