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29 March 2023
Published online 6 March 2023
Excess weight and poor metabolic health exacerbate DNA damage in breast tissues and further heighten cancer risks in women with inherited gene mutations.
Obesity is a well-known risk factor for breast cancer in women after menopause. This means that certain women who have a predisposition to breast cancer due to inherited mutations in BRCA genes may be at even higher risk if they are overweight.
This has now been investigated by an international collaboration, led by Kristy Brown at Weill Cornell Medicine, New York, and including Heba Zahid at Taibah University in Medina, Saudi Arabia. The team demonstrated that obesity and poor metabolic health are associated with significant DNA damage in milk glands in the breasts of women who carry a mutation in either of the BRCA1 or BRCA2 genes.
“Both BRCA1 and BRCA2 are involved in repairing DNA,” says Brown. “When women hold a mutation in one of these genes, cells are more likely to accumulate DNA damage over time and this can lead to tumour development. We examined whether obesity-related factors induce DNA damage and whether they contribute to heightened cancer risk for these women.”
Zahid has spent years developing techniques to assess biomarkers of risk in breast and ovarian tissues, and her collaboration with Brown spans almost a decade. Obesity induces multiple changes to the microenvironment in breast fat tissues, including disruption to the balance of hormones such as oestrogen and insulin. These changes have a knock-on effect on neighbouring breast epithelial cells.
The research team analysed human tissue samples from women carrying a BRCA mutation and found that elevated BMI (body mass index) and markers of poor metabolic health were positively correlated with increased DNA damage in breast epithelial cells. Gene expression in breast epithelial and fat cells was also altered.
“We identified several factors that were driving damage in the breast glands of these individuals, including elevated insulin and breast oestrogen levels,” says Brown. “In further experiments on a mouse model of BRCA mutation, we demonstrated that a high fat diet led to a similar increase in DNA damage. The mice [that were] fed a high fat diet also had a higher rate of mammary cancer development than controls.”
The team showed that DNA damage could be reversed using the anti-diabetic drug metformin. The drug not only regulated insulin levels but also reduced the production of oestrogen locally in the breast.
“Our results suggest that modifying lifestyle or using drugs to target specific factors may reduce breast cancer risk in women who carry mutations in BRCA1 or BRCA2. This is particularly important for women who opt not to have risk reducing surgery,” says Brown.
Bhardwaj, P. et al. Obesity promotes breast epithelium DNA damage in women carrying a germline mutation in BRCA1 or BRCA2. Sci. Trans. Med. 15, eade1857 (2023).