PMID- 24633304 OWN - NLM STAT- MEDLINE DCOM- 20140529 LR - 20220316 IS - 1546-170X (Electronic) IS - 1078-8956 (Print) IS - 1078-8956 (Linking) VI - 20 IP - 4 DP - 2014 Apr TI - Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression. PG - 360-7 LID - 10.1038/nm.3497 [doi] AB - 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 beta-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. FAU - Mouw, Janna K AU - Mouw JK AD - Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco (UCSF), San Francisco, California, USA. FAU - Yui, Yoshihiro AU - Yui Y AD - Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco (UCSF), San Francisco, California, USA. FAU - Damiano, Laura AU - Damiano L AD - Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco (UCSF), San Francisco, California, USA. FAU - Bainer, Russell O AU - Bainer RO AD - Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco (UCSF), San Francisco, California, USA. FAU - Lakins, Johnathon N AU - Lakins JN AD - Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco (UCSF), San Francisco, California, USA. FAU - Acerbi, Irene AU - Acerbi I AD - Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco (UCSF), San Francisco, California, USA. FAU - Ou, Guanqing AU - Ou G AUID- ORCID: 0000000238881902 AD - Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco (UCSF), San Francisco, California, USA. FAU - Wijekoon, Amanda C AU - Wijekoon AC AD - Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco (UCSF), San Francisco, California, USA. FAU - Levental, Kandice R AU - Levental KR AD - Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston-Medical School, Houston, Texas, USA. FAU - Gilbert, Penney M AU - Gilbert PM AD - Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada. FAU - Hwang, E Shelley AU - Hwang ES AD - Department of Surgery, Duke University Comprehensive Cancer Center, Durham, North Carolina, USA. FAU - Chen, Yunn-Yi AU - Chen YY AD - Department of Pathology, UCSF, San Francisco, California, USA. FAU - Weaver, Valerie M AU - Weaver VM AD - 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. LA - eng GR - R01 CA085492/CA/NCI NIH HHS/United States GR - R01 CA138818/CA/NCI NIH HHS/United States GR - U01 ES019458/ES/NIEHS NIH HHS/United States GR - U54 CA143836/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20140316 PL - United States TA - Nat Med JT - Nature medicine JID - 9502015 RN - 0 (Homeodomain Proteins) RN - 0 (MIRN18A microRNA, human) RN - 0 (MicroRNAs) RN - 0 (Oncogene Protein p55(v-myc)) RN - 0 (beta Catenin) RN - 0 (homeobox protein HOXA9) RN - EC 3.1.3.67 (PTEN Phosphohydrolase) SB - IM CIN - Nat Rev Cancer. 2014 May;14(5):296. PMID: 24705651 MH - Animals MH - Breast Neoplasms MH - Cell Line MH - Disease Progression MH - *Elasticity MH - Extracellular Matrix/genetics/*metabolism MH - Female MH - *Gene Expression Regulation, Neoplastic MH - Homeodomain Proteins/metabolism MH - Humans MH - Mammary Glands, Animal/metabolism MH - Mammary Glands, Human/metabolism MH - Mice MH - MicroRNAs/*genetics/physiology MH - Neoplasm Metastasis/genetics MH - Oncogene Protein p55(v-myc)/metabolism MH - PTEN Phosphohydrolase/*metabolism MH - *Tumor Microenvironment MH - beta Catenin/metabolism PMC - PMC3981899 MID - NIHMS566350 EDAT- 2014/03/19 06:00 MHDA- 2014/05/30 06:00 PMCR- 2014/10/01 CRDT- 2014/03/18 06:00 PHST- 2013/07/30 00:00 [received] PHST- 2014/02/10 00:00 [accepted] PHST- 2014/03/18 06:00 [entrez] PHST- 2014/03/19 06:00 [pubmed] PHST- 2014/05/30 06:00 [medline] PHST- 2014/10/01 00:00 [pmc-release] AID - nm.3497 [pii] AID - 10.1038/nm.3497 [doi] PST - ppublish SO - Nat Med. 2014 Apr;20(4):360-7. doi: 10.1038/nm.3497. Epub 2014 Mar 16.