Title |
Obesity promotes breast epithelium DNA damage in women carrying a germline mutation in BRCA1 or BRCA2
|
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Published in |
Science Translational Medicine, February 2023
|
DOI | 10.1126/scitranslmed.ade1857 |
Pubmed ID | |
Authors |
Priya Bhardwaj, Neil M Iyengar, Heba Zahid, Katharine M Carter, Dong Jun Byun, Man Ho Choi, Qi Sun, Oleksandr Savenkov, Charalambia Louka, Catherine Liu, Phoebe Piloco, Monica Acosta, Rohan Bareja, Olivier Elemento, Miguel Foronda, Lukas E Dow, Sofya Oshchepkova, Dilip D Giri, Michael Pollak, Xi Kathy Zhou, Benjamin D Hopkins, Ashley M Laughney, Melissa K Frey, Lora Hedrick Ellenson, Monica Morrow, Jason A Spector, Lewis C Cantley, Kristy A Brown |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 50 | 25% |
Canada | 7 | 3% |
United Kingdom | 7 | 3% |
Germany | 5 | 2% |
Australia | 5 | 2% |
Spain | 5 | 2% |
India | 4 | 2% |
Mexico | 3 | 1% |
Chile | 3 | 1% |
Other | 22 | 11% |
Unknown | 93 | 46% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 131 | 64% |
Scientists | 54 | 26% |
Practitioners (doctors, other healthcare professionals) | 15 | 7% |
Science communicators (journalists, bloggers, editors) | 3 | 1% |
Unknown | 1 | <1% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 44 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 11 | 25% |
Student > Bachelor | 4 | 9% |
Unspecified | 3 | 7% |
Student > Ph. D. Student | 3 | 7% |
Student > Master | 3 | 7% |
Other | 7 | 16% |
Unknown | 13 | 30% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 9 | 20% |
Medicine and Dentistry | 7 | 16% |
Agricultural and Biological Sciences | 5 | 11% |
Unspecified | 3 | 7% |
Pharmacology, Toxicology and Pharmaceutical Science | 1 | 2% |
Other | 5 | 11% |
Unknown | 14 | 32% |