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

Sci Transl Med. 2023 Feb 22;15(684):eade1857. doi: 10.1126/scitranslmed.ade1857. Epub 2023 Feb 22.


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. Whether elevated BMI is a risk factor for women with a germline mutation in BRCA1 or BRCA2 is less clear because of inconsistent findings from epidemiological studies and a lack of mechanistic studies in this population. Here, we 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 estrogen biosynthesis, which affected neighboring breast epithelial cells. In breast tissue explants cultured from women carrying a BRCA mutation, we found that blockade of estrogen biosynthesis or estrogen 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 signaling of these factors with a leptin-neutralizing antibody or PI3K inhibitor, respectively, decreased DNA damage. Furthermore, we show that increased adiposity was associated with mammary gland DNA damage and increased penetrance of mammary tumors in Brca1+/- mice. Overall, our 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 estrogen or metabolic dysfunction may reduce the risk of breast cancer in this population.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • BRCA1 Protein / genetics
  • BRCA2 Protein
  • Breast Neoplasms* / pathology
  • DNA Damage
  • Epithelium / pathology
  • Estrogens
  • Female
  • Germ-Line Mutation
  • Humans
  • Leptin
  • Mammary Glands, Human* / pathology
  • Mice
  • Mutation
  • Obesity
  • Phosphatidylinositol 3-Kinases
  • Tumor Microenvironment


  • Leptin
  • Phosphatidylinositol 3-Kinases
  • BRCA2 Protein
  • BRCA1 Protein
  • Estrogens
  • BRCA1 protein, human
  • BRCA2 protein, human