Obesity may raise breast cancer risk in BRCA-mutated women 2023


According to a recent multi-institutional translational study led by scientists at Weill Cornell Medical, obesity may induce DNA damage in the breast tissue of women with BRCA1 or BRCA2 mutations, potentially contributing to the development of breast cancer in an already high-risk population.

The study, which was published in the 22 February edition of Science Translational Medicine, implies that weight control and drugs that improve metabolic health may be significant components of preventative treatment for women with these genetic abnormalities, though further research is required.

Women with BRCA mutations may be at a greater risk of developing breast cancer

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, according to the study’s senior author, Dr. Kristy A. Brown, an associate professor of biochemistry in medicine at Weill Cornell Medicine.

Dr. Priya Bhardwaj, the paper’s first author and a doctoral candidate at the Weill Cornell Graduate School of Medicine at the time the research was conducted, stated that prior epidemiological findings regarding the effect of body weight on breast cancer development in BRCA mutation carriers are inconclusive. “Our research gives mechanistic information to doctors regarding the potential benefits of acting on the metabolic side of the breast cancer disease process,” she explained.

The researchers examined noncancerous breast tissue samples from mastectomy patients with either BRCA1 or BRCA2 mutations. The research population comprised women with a body mass index (BMI) below 25 kg/m2 and those with a BMI of 25 or more, who were classified as overweight or obese.

Using immunofluorescence, the researchers discovered that a higher BMI in women with BRCA mutations was associated with DNA damage in the milk glands. They discovered that the metabolic hormones leptin and insulin, as well as the hormone estrogen, which is usually associated with the development of breast cancer, were responsible for this DNA damage.

In addition, the investigators discovered that metformin might prevent DNA damage in tissue samples in the laboratory. This medicine, which is routinely used to treat type 2 diabetes, is also known to inhibit aromatase–the enzyme responsible for estrogen manufacturing.

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

In addition to their tissue tests, the researchers evaluated mice with BRCA1 mutations to see if an increase in DNA damage is related to the development of malignant tumors. The researchers discovered that obese mice with metabolic dysfunction had greater tumor development rates than lean mice. “Not only did fat mice acquire tumors earlier, but they also formed tumors at a greater rate overall,” Dr. Bhardwaj explained.

Dr. Brown stated that this study contributes to a better understanding of the implications of lifestyle, obesity, and metabolic health on the development of cancer in high-risk groups. The researchers intend to do more research on the processes that cause DNA damage in the breast tissue of women with BRCA mutations and aim to stimulate clinical trials of lifestyle modifications or metformin in these individuals.

“This line of inquiry may extend beyond BRCA1 and BRCA2 mutation carriers,” Dr. Brown said, adding, “It may potentially have implications for other hereditary malignancies or cancer types.”

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