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Sci Transl Med. 2015 Aug 19;7(301):301ra130. doi: 10.1126/scitranslmed.3010467.

Obesity-dependent changes in interstitial ECM mechanics promote breast tumorigenesis.

Author information

1
Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.
2
Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
3
Department of Materials Science and Engineering, Cornell University, Ithaca, NY 14853, USA.
4
Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. Department of Materials Science and Engineering, Cornell University, Ithaca, NY 14853, USA.
5
Department of Biological and Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA.
6
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
7
Department of Healthcare Policy and Research, Weill Cornell Medical College, New York, NY 10065, USA.
8
Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10065, USA.
9
Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. Kavli Institute at Cornell for Nanoscale Science, Cornell University, Ithaca, NY 14853, USA. cf99@cornell.edu.

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 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.

PMID:
26290412
PMCID:
PMC4837896
DOI:
10.1126/scitranslmed.3010467
[Indexed for MEDLINE]
Free PMC Article

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