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

TitleObesity-dependent changes in interstitial ECM mechanics promote breast tumorigenesis.
Publication TypeJournal Article
Year of Publication2015
AuthorsSeo BRi, Bhardwaj P, Choi S, Gonzalez J, Eguiluz RCAndresen, Wang K, Mohanan S, Morris PG, Du B, Zhou XK, Vahdat LT, Verma A, Elemento O, Hudis CA, Williams RM, Gourdon D, Dannenberg AJ, Fischbach C
JournalSci Transl Med
Volume7
Issue301
Pagination301ra130
Date Published2015 Aug 19
ISSN1946-6242
KeywordsAdipose Tissue, Animals, Breast Neoplasms, Cell Differentiation, Cell Transformation, Neoplastic, Cells, Cultured, Extracellular Matrix, Female, Humans, Mice, Mice, Obese, Obesity
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.

DOI10.1126/scitranslmed.3010467
Alternate JournalSci Transl Med
PubMed ID26290412
PubMed Central IDPMC4837896
Grant ListR01CA154481 / CA / NCI NIH HHS / United States
U54CA143876 / CA / NCI NIH HHS / United States
R01 CA185293 / CA / NCI NIH HHS / United States
R21CA161532 / CA / NCI NIH HHS / United States
2UL1TR000457-06 / TR / NCATS NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
U54 CA143876 / CA / NCI NIH HHS / United States
1S10RR025502 / RR / NCRR NIH HHS / United States
S10 RR025502 / RR / NCRR NIH HHS / United States
R21 CA161532 / CA / NCI NIH HHS / United States
R01 CA154481 / CA / NCI NIH HHS / United States
R01CA185293 / CA / NCI NIH HHS / United States
S10OD010605 / OD / NIH HHS / United States
UL1 TR000457 / TR / NCATS NIH HHS / United States
S10 OD010605 / OD / NIH HHS / United States