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.
Priya Bhardwaj  1 ,  Neil M Iyengar  1  2 ,  Heba Zahid  3 ,  Katharine M Carter  1 ,  Dong Jun Byun  4 ,  Man Ho Choi  4 ,  Qi Sun  5 ,  Oleksandr Savenkov  6 ,  Charalambia Louka  1 ,  Catherine Liu  1 ,  Phoebe Piloco  1 ,  Monica Acosta  1 ,  Rohan Bareja  7 ,  Olivier Elemento  7 ,  Miguel Foronda  8 ,  Lukas E Dow  1  9 ,  Sofya Oshchepkova  1 ,  Dilip D Giri  10 ,  Michael Pollak  11 ,  Xi Kathy Zhou  6 ,  Benjamin D Hopkins  12 ,  Ashley M Laughney  9 ,  Melissa K Frey  13 ,  Lora Hedrick Ellenson  10 ,  Monica Morrow  14 ,  Jason A Spector  15 ,  Lewis C Cantley  9 ,  Kristy A Brown  1  9
Affiliations
  • 1. Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
  • 2. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 3. Department of Medical Laboratory Technology, College of Applied Medical Science, Taibah University, Medina 42353, Saudi Arabia.
  • 4. Center for Advanced Biomolecular Recognition, Korea Institute of Science and Technology, Seoul 02792, Korea.
  • 5. Computational Biology Service Unit of Life Sciences Core Laboratories Center, Cornell University, Ithaca, NY 14853, USA.
  • 6. Department of Population Health Sciences, Weill Cornell Medicine, New York, NY 10065, USA.
  • 7. Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
  • 8. Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 9. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
  • 10. Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 11. Departments of Medicine and Oncology, McGill University, Montreal, Canada.
  • 12. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 13. Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10065, USA.
  • 14. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 15. Laboratory of Bioregenerative Medicine and Surgery, Weill Cornell Medicine, New York, NY 10065, USA.
PMID: 36812344 DOI: 10.1126/scitranslmed.ade1857
Abstract

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.

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