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

Nature Medicine volume 20, pages 360–367 (2014)Cite this article

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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.

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Figure 1: ECM stiffness modulates miRNA expression in culture and in vivo.
Figure 2: ECM stiffness promotes malignancy by inducing miR-18a to reduce PTEN and enhance PI3K activity.
Figure 3: ECM stiffness promotes malignancy by inducing miR-18a to reduce HOXA9 expression.
Figure 4: ECM stiffness promotes malignancy by preventing HOXA9-dependent PTEN transcription.
Figure 5: Tissue stiffness engages mechanotransduction signaling pathways to promote miR-18a–dependent malignancy.
Figure 6: Breast malignancy associates with increased miR-18a and reduced PTEN expression.

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Acknowledgements

We thank the members of the Weaver and N. Boudreau labs for helpful discussions. Atomic force microscopy analysis of the PyMT samples was performed by H. Yu. Animal handling was supported by L. Korets. miRNA and antagomir constructs were provided by M. Scherr at the Medical School Hannover. PTEN proximal promoter constructs were provided by C. Eng at the Genomic Medical Institute. LOX inhibitory antibodies were provided by A. Giaccia at the Stanford University School of Medicine. HOXA9 was provided by T. Nakamura at the Japanese Foundation for Cancer Research. This work was supported by US Department of Defense Breast Cancer Research Program (DOD BCRP) grant W81XWH-07-1-0538 (J.K.M.), Susan G. Komen Postdoctoral Fellowship PDF12230246 (I.A.), US National Science Foundation Graduate Research Fellowship (G.O.), DOD BCRP grants W81XWH-05-1-0330 and W81XWH-13-1-0216 (V.M.W.), US National Institutes of Health NCI grants R01 CA138818, U54 CA143836, R01 CA085492 and U01 ES019458 (V.M.W.) and Susan G. Komen grant KG110560PP (V.M.W. and E.S.W.).

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Authors and Affiliations

  1. Department of Surgery, Center for Bioengineering and Tissue Regeneration, University of California San Francisco (UCSF), San Francisco, California, USA

    Janna K Mouw, Yoshihiro Yui, Laura Damiano, Russell O Bainer, Johnathon N Lakins, Irene Acerbi, Guanqing Ou, Amanda C Wijekoon & Valerie M Weaver

  2. Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston–Medical School, Houston, Texas, USA

    Kandice R Levental

  3. Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada

    Penney M Gilbert

  4. Department of Surgery, Duke University Comprehensive Cancer Center, Durham, North Carolina, USA

    E Shelley Hwang

  5. Department of Pathology, UCSF, San Francisco, California, USA

    Yunn-Yi Chen

  6. Department of Anatomy and Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, California, USA

    Valerie M Weaver

  7. Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, California, USA

    Valerie M Weaver

  8. UCSF Helen Diller Comprehensive Cancer Center, UCSF, San Francisco, California, USA

    Valerie M Weaver

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Contributions

J.K.M., Y.Y. and L.D. conducted PyMT and V737N mouse experiments. J.K.M., A.C.W. and K.R.L. fabricated and conducted experiments with the PA hydrogels. R.O.B. and J.K.M. performed the miRNA and large-scale gene expression analyses. J.N.L. designed and constructed expression constructs and the V737N transgenic mouse. J.K.M. and Y.Y. performed immunofluorescence imaging, and G.O. performed the ImageJ analyses. I.A. performed AFM measurements. E.S.H. collected the human patient samples and aided in the interpretation of the data. Y.-Y.C. aided with pathological breast cancer subtyping. P.M.G. conducted the HOXA9 microarray analysis25. V.M.W. and J.K.M. wrote the manuscript with input from all authors.

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Correspondence to Valerie M Weaver.

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Mouw, J., Yui, Y., Damiano, L. et al. Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression. Nat Med 20, 360–367 (2014). https://doi.org/10.1038/nm.3497

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