Obesity-dependent changes in interstitial ECM mechanics promote breast tumorigenesis

Seo, B. R. et al. (2015) Obesity-dependent changes in interstitial ECM mechanics promote breast tumorigenesis. Science Translational Medicine, 7(301), 301ra130. (doi: 10.1126/scitranslmed.3010467) (PMID:26290412) (PMCID:PMC4837896)

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226110.pdf - Accepted Version



Obesity and extracellular matrix (ECM) density are considered independent risk and prognostic factors for breast cancer. Whether they are functionally linked is uncertain. We investigated the hypothesis that obesity enhances local myofibroblast content in mammary adipose tissue and that these stromal changes increase malignant potential by enhancing interstitial ECM stiffness. Indeed, mammary fat of both diet- and genetically induced mouse models of obesity were enriched for myofibroblasts and stiffness-promoting ECM components. These differences were related to varied adipose stromal cell (ASC) characteristics because ASCs isolated from obese mice contained more myofibroblasts and deposited denser and stiffer ECMs relative to ASCs from lean control mice. Accordingly, decellularized matrices from obese ASCs stimulated mechanosignaling and thereby the malignant potential of breast cancer cells. Finally, the clinical relevance and translational potential of our findings were supported by analysis of patient specimens and the observation that caloric restriction in a mouse model reduces myofibroblast content in mammary fat. Collectively, these findings suggest that obesity-induced interstitial fibrosis promotes breast tumorigenesis by altering mammary ECM mechanics with important potential implications for anticancer therapies.

Item Type:Articles
Additional Information:This study was funded by NIH/NCI (National Cancer Institute) [U54CA143876, R01CA185293, R01CA154481, R21CA161532, 1S10RR025502, and S10OD010605 (BRC)], the National Science Foundation [CMMI 1031068, DMR-1120296 (CCMR)], the Breast Cancer Research Foundation, the Botwinick-Wolfensohn Foundation (in memory of Mr. and Mrs. Benjamin Botwinick), and 2UL1TR000457-06 of the Clinical and Translational Science Center at Weill Cornell Medical College.
Glasgow Author(s) Enlighten ID:Gourdon, Professor Delphine
Authors: Seo, B. R., Bhardwaj, P., Choi, S., Gonzalez, J., Andresen Eguiluz, R. C., Wang, K., Mohanan, S., Morris, P. G., Du, B., Zhou, X. K., Vahdat, L. T., Verma, A., Elemento, O., Hudis, C. A., Williams, R. M., Gourdon, D., Dannenberg, A. J., and Fischbach, C.
College/School:College of Science and Engineering > School of Engineering > Biomedical Engineering
Journal Name:Science Translational Medicine
Publisher:American Association for the Advancement of Science
ISSN (Online):1946-6242

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