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

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

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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