Format

Send to

Choose Destination
See comment in PubMed Commons below
Nat Med. 2014 Apr;20(4):360-7. doi: 10.1038/nm.3497. Epub 2014 Mar 16.

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

Author information

1
Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco (UCSF), San Francisco, California, USA.
2
Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston-Medical School, Houston, Texas, USA.
3
Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
4
Department of Surgery, Duke University Comprehensive Cancer Center, Durham, North Carolina, USA.
5
Department of Pathology, UCSF, San Francisco, California, USA.
6
1] Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco (UCSF), San Francisco, California, USA. [2] Department of Anatomy and Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, California, USA. [3] Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, California, USA. [4] UCSF Helen Diller Comprehensive Cancer Center, UCSF, San Francisco, California, USA.

Abstract

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.

PMID:
24633304
PMCID:
PMC3981899
DOI:
10.1038/nm.3497
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Nature Publishing Group Icon for PubMed Central
    Loading ...
    Support Center