Regulation of adipose oestrogen output by mechanical stress

Sagar Ghosh, Keith Ashcraft, Md Jamiul Jahid, Craig April, Cyrus M. Ghajar, Jianhua Ruan, Howard Wang, Megan Foster, Daniel C. Hughes, Amelie G. Ramirez, Tim Huang, Jian Bing Fan, Yanfen Hu, Rong Li

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Adipose stromal cells are the primary source of local oestrogens in adipose tissue, aberrant production of which promotes oestrogen receptor-positive breast cancer. Here we show that extracellular matrix compliance and cell contractility are two opposing determinants for oestrogen output of adipose stromal cells. Using synthetic extracellular matrix and elastomeric micropost arrays with tunable rigidity, we find that increasing matrix compliance induces transcription of aromatase, a rate-limiting enzyme in oestrogen biosynthesis. This mechanical cue is transduced sequentially by discoidin domain receptor 1, c-Jun N-terminal kinase 1, and phosphorylated JunB, which binds to and activates two breast cancer-associated aromatase promoters. In contrast, elevated cell contractility due to actin stress fibre formation dampens aromatase transcription. Mechanically stimulated stromal oestrogen production enhances oestrogen-dependent transcription in oestrogen receptor-positive tumour cells and promotes their growth. This novel mechanotransduction pathway underlies communications between extracellular matrix, stromal hormone output, and cancer cell growth within the same microenvironment.

Original languageEnglish (US)
Article number1821
JournalNature communications
Volume4
DOIs
StatePublished - Jun 10 2013

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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