title: Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression.
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.
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco (UCSF), San Francisco, California, USA.
authors.forename: Janna K
authors.initials: JK
authors.lastname: Mouw
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco (UCSF), San Francisco, California, USA.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yui
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco (UCSF), San Francisco, California, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Damiano
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco (UCSF), San Francisco, California, USA.
authors.forename: Russell O
authors.initials: RO
authors.lastname: Bainer
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco (UCSF), San Francisco, California, USA.
authors.forename: Johnathon N
authors.initials: JN
authors.lastname: Lakins
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco (UCSF), San Francisco, California, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Acerbi
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco (UCSF), San Francisco, California, USA.
authors.forename: Guanqing
authors.identifier: 0000000238881902
authors.initials: G
authors.lastname: Ou
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco (UCSF), San Francisco, California, USA.
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Wijekoon
authors.affiliation: Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston-Medical School, Houston, Texas, USA.
authors.forename: Kandice R
authors.initials: KR
authors.lastname: Levental
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Penney M
authors.initials: PM
authors.lastname: Gilbert
authors.affiliation: Department of Surgery, Duke University Comprehensive Cancer Center, Durham, North Carolina, USA.
authors.forename: E Shelley
authors.initials: ES
authors.lastname: Hwang
authors.affiliation: Department of Pathology, UCSF, San Francisco, California, USA.
authors.forename: Yunn-Yi
authors.initials: YY
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Weaver
mesh_terms: D000818:Animals; D001943:Breast Neoplasms; D002460:Cell Line; D018450:Disease Progression; D004548:Elasticity; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008321:Mammary Glands, Animal / Q000378:metabolism; D042361:Mammary Glands, Human / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000502:physiology; D009362:Neoplasm Metastasis / Q000235:genetics; D016274:Oncogene Protein p55(v-myc) / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D059016:Tumor Microenvironment; D051176:beta Catenin / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C522576:MIRN18A microRNA, human; D035683:MicroRNAs; D016274:Oncogene Protein p55(v-myc); D051176:beta Catenin; C097899:homeobox protein HOXA9; D051059:PTEN Phosphohydrolase