Obesity As A Risk Factor For Breast Cancer

Obesity promotes breast epithelium DNA damage in women carrying a germline mutation in BRCA1 or BRCA2

Obesity, defined as a body mass index (BMI) ≥ 30, is an established risk factor for breast cancer among women in the general population after menopause.

Bhardwaj et al., (2023) show that DNA damage in normal breast epithelia of women carrying a BRCA mutation is positively correlated with BMI and with biomarkers of metabolic dysfunction. In addition, RNA sequencing showed obesity-associated alterations to the breast adipose microenvironment of BRCA mutation carriers, including activation of oestrogen biosynthesis, which affected neighbouring breast epithelial cells. 

In breast tissue explants cultured from women carrying a BRCA mutation, we found that blockade of oestrogen biosynthesis or oestrogen receptor activity decreased DNA damage. Additional obesity-associated factors, including leptin and insulin, increased DNA damage in human BRCA heterozygous epithelial cells, and inhibiting the signalling of these factors with a leptin-neutralising antibody or PI3K inhibitor, respectively, decreased DNA damage. 

Furthermore, they show that increased adiposity was associated with mammary gland DNA damage and increased penetrance of mammary tumours in BRCA1+/− mice. 

Overall, their results provide mechanistic evidence in support of a link between elevated BMI and breast cancer development in BRCA mutation carriers. This suggests that maintaining a lower body weight or pharmacologically targeting oestrogen or metabolic dysfunction may reduce the risk of breast cancer in this population.

Overweight enhances the incidence of brain tumours, kidney cancer, endometrial cancer, ovarian cancer, multiple myeloma, bladder cancer and liver cancer.

Obesity was related to the increased incidence of brain tumours, cervical cancer, kidney cancer, endometrial cancer, esophageal cancer, gastric cancer, ovarian cancer, multiple myeloma, gallbladder cancer, bladder cancer, colorectal cancer, liver cancer, thyroid cancer and Hodgkin’s lymphoma.
Moreover, dose-response analysis was conducted by 10 studies, and the results demonstrated that each 5 Kg/m2 increase in BMI was associated with a 1.01- to 1.13-fold increased risk of general brain tumours, multiple myeloma, bladder cancer, pancreatic cancer, breast cancer, and non-Hodgkin’s lymphoma.

Every 1 Kg/m2 increase in BMI was linked to 6% and 4% increases in the risk of kidney cancer and gallbladder cancer, respectively.

Reference:

Science Translational Medicine 22 Feb 2023 Vol 15, Issue 684 DOI: 10.1126/scitranslmed.ade1857