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

TitleObesity promotes breast epithelium DNA damage in women carrying a germline mutation in BRCA1 or BRCA2.
Publication TypeJournal Article
Year of Publication2023
AuthorsBhardwaj P, Iyengar NM, Zahid H, Carter KM, Byun DJun, Choi MHo, Sun Q, Savenkov O, Louka C, Liu C, Piloco P, Acosta M, Bareja R, Elemento O, Foronda M, Dow LE, Oshchepkova S, Giri DD, Pollak M, Zhou XKathy, Hopkins BD, Laughney AM, Frey MK, Ellenson LHedrick, Morrow M, Spector JA, Cantley LC, Brown KA
JournalSci Transl Med
Volume15
Issue684
Paginationeade1857
Date Published2023 Feb 22
ISSN1946-6242
KeywordsAnimals, BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, DNA Damage, Epithelium, Estrogens, Female, Germ-Line Mutation, Humans, Leptin, Mammary Glands, Human, Mice, Mutation, Obesity, Phosphatidylinositol 3-Kinases, Tumor Microenvironment
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.

DOI10.1126/scitranslmed.ade1857
Alternate JournalSci Transl Med
PubMed ID36812344
Grant ListR01 CA215797 / CA / NCI NIH HHS / United States
F31 CA236306 / CA / NCI NIH HHS / United States
R35 CA197588 / CA / NCI NIH HHS / United States
KL2 TR002385 / TR / NCATS NIH HHS / United States
T32 GM007739 / GM / NIGMS NIH HHS / United States

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