Obesity-dependent changes in interstitial ECM mechanics promote breast tumorigenesis

Bo Ri Seo, Priya Bhardwaj, Siyoung Choi, Jacqueline Gonzalez, Roberto C.Andresen Eguiluz, Karin Wang, Sunish Mohanan, Patrick G. Morris, Baoheng Du, Xi K. Zhou, Linda T. Vahdat, Akanksha Verma, Olivier Elemento, Clifford A. Hudis, Rebecca M. Williams, Delphine Gourdon, Andrew J. Dannenberg, Claudia Fischbach

Research output: Contribution to journalArticle

121 Scopus citations

Abstract

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 containedmoremyofibroblasts 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.

Original languageEnglish (US)
Article number3010467
JournalScience translational medicine
Volume7
Issue number301
DOIs
StatePublished - Aug 19 2015

ASJC Scopus subject areas

  • Medicine(all)

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