Editors' ChoiceCancer

Stiff Path to Malignancy

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Science Signaling  29 Apr 2014:
Vol. 7, Issue 323, pp. ec115
DOI: 10.1126/scisignal.2005417

Stiffening of the extracellular matrix is implicated in malignant transformation and tumor progression (see Seewaldt). Mouw et al. found that matrix stiffness inhibited the expression of tumor suppressor genes through a microRNA (miRNA)–mediated transcriptional circuit. In nonmalignant human mammary epithelial cell lines, the abundance of miR-18a, which is encoded by the polycistronic miR-17-92 cluster, and of the transcription factor MYC, which stimulates the expression of miR-17-92, was higher in cells cultured on stiff polyacrylamide gels containing recombinant basement membrane than in those grown on softer gels. miR-18a abundance was also increased in the mammary tissue of PyMT mice (a model for breast cancer), and miR-18a and MYC abundance was decreased in mice by inhibiting the cross-linking of collagen and elastin by lysyl oxidase, thereby preventing extracellular matrix stiffening. miR-18a inhibited the expression of the tumor suppressor PTEN and HOXA9 (which encodes a transcription factor), and HOXA9 stimulated the expression of PTEN. Knocking down HOXA9 decreased PTEN expression in cells cultured on soft gels, whereas overexpressing HOXA9 prevented the stiff gel-induced decrease in PTEN expression. Nuclear β-catenin promotes the transcription of MYC, and nuclear localization of β-catenin was increased in tumors in PyMT mice or when cells were grown on the stiffer matrix. Integrin signaling stimulates the phosphorylation and activation of focal adhesion kinase (FAK), which in turn promotes the nuclear localization of β-catenin. In cells cultured on a stiff substrate, FAK activation was increased, and inhibiting FAK reduced miR-18a and increased HOXA9 and PTEN abundance. In mice expressing in a mammary tissue–specific manner an integrin subunit β1 mutant that enhances FAK activation, the abundance of nuclear β-catenin, MYC, and miR-18a were increased in mammary tissue, whereas that of HOXA9 and PTEN were decreased. In patient samples, the abundance of miR-18a was higher in breast tumor tissue than in normal breast tissue, and more aggressive luminal A-type tumors had greater miR-18a abundance, less HOXA9 and PTEN abundance, and were stiffer (as assessed by atomic force microscopy) than less aggressive luminal B-type tumors. miR-18a abundance in patient tumors inversely correlated with disease-free survival. These findings show how stiffening in the microenvironment promotes malignant changes in breast epithelial cells.

J. K. Mouw, Y. Yui, L. Damiano, R. O. Bainer, J. N. Lakins, I. Acerbi, G. Ou, A. C. Wijekoon, K. R. Levental, P. M. Gilbert, E. S. Hwang, Y.-Y. Chen, V. M. Weaver, Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression. Nat. Med. 20, 360–367 (2014). [PubMed]

V. Seewaldt, ECM stiffness paves the way for tumor cells. Nat. Med. 20, 332–333 (2014). [Pub Med]