Obesity promotes breast epithelium DNA damage in women carrying a germline mutation in BRCA1 or BRCA2 Journal Article
| Authors: | Bhardwaj, P.; Iyengar, N. M.; Zahid, H.; Carter, K. M.; Byun, D. J.; Choi, M. H.; Sun, Q.; Savenkov, O.; Louka, C.; Liu, C.; Piloco, P.; Acosta, M.; Bareja, R.; Elemento, O.; Foronda, M.; Dow, L. E.; Oshchepkova, S.; Giri, D. D.; Pollak, M.; Zhou, X. K.; Hopkins, B. D.; Laughney, A. M.; Frey, M. K.; Ellenson, L. H.; Morrow, M.; Spector, J. A.; Cantley, L. C.; Brown, K. A. |
| Article Title: | Obesity promotes breast epithelium DNA damage in women carrying a germline mutation in BRCA1 or BRCA2 |
| 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. |
| Keywords: | genetics; mutation; leptin; mouse; animal; animals; mice; dna damage; estrogen; estrogens; obesity; pathology; breast neoplasms; brca1 protein; brca2 protein; phosphatidylinositol 3 kinase; breast tumor; epithelium; brca1 protein, human; germ-line mutation; mammary gland; mammary glands, human; tumor microenvironment; phosphatidylinositol 3-kinases; germline mutation; brca2 protein, human; humans; human; female |
| Journal Title: | Science Translational Medicine |
| Volume: | 15 |
| Issue: | 684 |
| ISSN: | 1946-6234 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2023-02-22 |
| Start Page: | eade1857 |
| Language: | English |
| DOI: | 10.1126/scitranslmed.ade1857 |
| PUBMED: | 36812344 |
| PROVIDER: | scopus |
| PMCID: | PMC10557057 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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