Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression.

Published

Journal Article

Tissue mechanics regulate development and homeostasis and are consistently modified in tumor progression. Nevertheless, the fundamental molecular mechanisms through which altered mechanics regulate tissue behavior and the clinical relevance of these changes remain unclear. We demonstrate that increased matrix stiffness modulates microRNA expression to drive tumor progression through integrin activation of β-catenin and MYC. Specifically, in human and mouse tissue, increased matrix stiffness induced miR-18a to reduce levels of the tumor suppressor phosphatase and tensin homolog (PTEN), both directly and indirectly by decreasing levels of homeobox A9 (HOXA9). Clinically, extracellular matrix stiffness correlated directly and significantly with miR-18a expression in human breast tumor biopsies. miR-18a expression was highest in basal-like breast cancers in which PTEN and HOXA9 levels were lowest, and high miR-18a expression predicted poor prognosis in patients with luminal breast cancers. Our findings identify a mechanically regulated microRNA circuit that can promote malignancy and suggest potential prognostic roles for HOXA9 and miR-18a levels in stratifying patients with luminal breast cancers.

Full Text

Duke Authors

Cited Authors

  • Mouw, JK; Yui, Y; Damiano, L; Bainer, RO; Lakins, JN; Acerbi, I; Ou, G; Wijekoon, AC; Levental, KR; Gilbert, PM; Hwang, ES; Chen, Y-Y; Weaver, VM

Published Date

  • April 2014

Published In

Volume / Issue

  • 20 / 4

Start / End Page

  • 360 - 367

PubMed ID

  • 24633304

Pubmed Central ID

  • 24633304

Electronic International Standard Serial Number (EISSN)

  • 1546-170X

Digital Object Identifier (DOI)

  • 10.1038/nm.3497

Language

  • eng

Conference Location

  • United States