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

Autor:	Bhardwaj P; Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA., Iyengar NM; Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Zahid H; Department of Medical Laboratory Technology, College of Applied Medical Science, Taibah University, Medina 42353, Saudi Arabia., Carter KM; Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA., Byun DJ; Center for Advanced Biomolecular Recognition, Korea Institute of Science and Technology, Seoul 02792, Korea., Choi MH; Center for Advanced Biomolecular Recognition, Korea Institute of Science and Technology, Seoul 02792, Korea., Sun Q; Computational Biology Service Unit of Life Sciences Core Laboratories Center, Cornell University, Ithaca, NY 14853, USA., Savenkov O; Department of Population Health Sciences, Weill Cornell Medicine, New York, NY 10065, USA., Louka C; Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA., Liu C; Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA., Piloco P; Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA., Acosta M; Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA., Bareja R; Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10065, USA., Elemento O; Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10065, USA., Foronda M; Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Dow LE; Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA., Oshchepkova S; Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA., Giri DD; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Pollak M; Departments of Medicine and Oncology, McGill University, Montreal, Canada., Zhou XK; Department of Population Health Sciences, Weill Cornell Medicine, New York, NY 10065, USA., Hopkins BD; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Laughney AM; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA., Frey MK; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10065, USA., Ellenson LH; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Morrow M; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Spector JA; Laboratory of Bioregenerative Medicine and Surgery, Weill Cornell Medicine, New York, NY 10065, USA., Cantley LC; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA., Brown KA; Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2023 Feb 22; Vol. 15 (684), pp. eade1857. Date of Electronic Publication: 2023 Feb 22.
DOI:	10.1126/scitranslmed.ade1857
Abstrakt:	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.
Databáze:	MEDLINE
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