Obesity may spur DNA damage in the breast tissue of patients who carry BRCA1 or BRCA2 mutations, possibly contributing to breast cancer development in patients who are already at a higher risk of the disease, according to a new study published by Bhardwaj et al in Science Translational Medicine. The findings suggest that weight management and medications that improve metabolic health may be an important part of preventive care for patients with these genetic mutations.
Background
Obesity and poor metabolic health are known modifiable risk factors that may contribute to the development of breast cancer in the general population.
“[W]hether these modifiable risk factors contribute to breast cancer development in [patients with] BRCA mutations has been largely unknown,” explained senior study author Kristy A. Brown, PhD, Associate Professor of Biochemistry in Medicine and the Emilie Lippmann and Janice Jacobs McCarthy Research Scholar in Breast Cancer in the Department of Medicine at Weill Cornell Medicine, New York. Previous epidemiologic studies of the impact of body weight on breast cancer development in patients with BRCA mutations have resulted in unclear findings.
“Our research provides clinicians with mechanistic evidence of the possible benefits of intervening on the metabolic side of the breast cancer disease process,” highlighted first study author Priya Bhardwaj, PhD, who was a PhD candidate at the Weill Cornell Graduate School of Medical Sciences at the time of the study’s publication.
Study Methods and Results
In the new multi-institutional translational study, the researchers analyzed noncancerous breast tissue samples from patients who had either BRCA1 or BRCA2 mutations and had undergone mastectomies. The study population included patients with a body mass index (BMI) below 25 kg/m2 and those with a BMI of 25 kg/m2 or higher—categorized as overweight or obese.
Using immunofluorescence, the researchers found that a higher BMI in patients with BRCA mutations was positively correlated with DNA damage in the mammary glands. They determined that the metabolic hormones leptin and insulin as well as estrogen—which is commonly linked with breast cancer growth—were drivers of this type of DNA damage.
Further, the researchers 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 capable of suppressing the expression of the estrogen-biosynthesizing enzyme aromatase.
“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,” Dr. Brown emphasized. “However, we still need to determine which biomarkers can be used as clear indications of risk reduction … beyond closely following [patients in this population] for cancer development,” she added.
In addition to studying the noncancerous breast tissue samples, the researchers assessed mice with BRCA1 mutations to better understand whether an increase in DNA damage is associated with cancerous tumor growth. The researchers discovered that obese mice with metabolic dysfunction had higher rates of tumor formation than thin 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,” Dr. Bhardwaj underscored.
Conclusions
Overall, the researchers noted that their findings may contribute to a better appreciation of the effects of lifestyle, obesity, and metabolic health on breast cancer development in high-risk populations. The researchers plan to further study the mechanisms that drive DNA damage in the breast tissue of individuals 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 [patients with] BRCA1 and BRCA2 mutations. It may also have an impact on other hereditary cancers or cancer types,” Dr. Brown suggested.
The researchers concluded that individuals with BRCA mutations who maintain a lower body weight or who target estrogen or metabolic dysfunction with medications may be able to reduce their risk of developing breast cancer.
Disclosure: For full disclosures of the study authors, visit science.org.
