期刊
FASEB JOURNAL
卷 34, 期 6, 页码 8611-8624出版社
WILEY
DOI: 10.1096/fj.202000228RR
关键词
decorin; macrophages; mammary gland; obesity; transforming growth factor beta
资金
- National Cancer Institute (NCI) [R01 CA227542, P30 CA014520]
- National Institutes of Health (NIH) [T32 OD010423]
- Susan G. Komen (SGK) [CCR1532611]
Obesity is a risk factor for breast cancer in postmenopausal and high-risk premenopausal women. Changes within the obese breast microenvironment may increase breast cancer risk. Transforming growth factor beta-1 (TGF beta 1) is a major regulator of mammary epithelial stem/progenitor cells, and its activity is dysregulated under conditions of obesity. Using a high-fat diet model of obesity in mice and breast tissue from women, we observed that TGF beta 1 activity is reduced in breast epithelial cells in obesity. Breast ducts and lobules demonstrated increased decorin in the extracellular matrix (ECM) surrounding epithelial cells, and we observed that decorin and latent TGF beta 1 complexed together. Under conditions of obesity, macrophages expressed higher levels of decorin and were significantly increased in number surrounding breast epithelial cells. To investigate the relationship between macrophages and decorin expression, we treated obese mice with either IgG control or anti-F4/80 antibodies to deplete macrophages. Mice treated with anti-F4/80 antibodies demonstrated reduced decorin surrounding mammary ducts and enhanced TGF beta 1 activity within mammary epithelial cells. Given the role of TGF beta 1 as a tumor suppressor, reduced epithelial TGF beta 1 activity and enhanced TGF beta 1 within the ECM of obese mammary tissue may enhance breast cancer risk.
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