Mutant p53–associated myosin-X upregulation promotes breast cancer invasion and metastasis
Antti Arjonen, … , Heikki Joensuu, Johanna Ivaska
Antti Arjonen, … , Heikki Joensuu, Johanna Ivaska
Published February 3, 2014
Citation Information: J Clin Invest. 2014;124(3):1069-1082. https://doi.org/10.1172/JCI67280.
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Research Article Oncology

Mutant p53–associated myosin-X upregulation promotes breast cancer invasion and metastasis

Abstract

Mutations of the tumor suppressor TP53 are present in many forms of human cancer and are associated with increased tumor cell invasion and metastasis. Several mechanisms have been identified for promoting dissemination of cancer cells with TP53 mutations, including increased targeting of integrins to the plasma membrane. Here, we demonstrate a role for the filopodia-inducing motor protein Myosin-X (Myo10) in mutant p53–driven cancer invasion. Analysis of gene expression profiles from 2 breast cancer data sets revealed that MYO10 was highly expressed in aggressive cancer subtypes. Myo10 was required for breast cancer cell invasion and dissemination in multiple cancer cell lines and murine models of cancer metastasis. Evaluation of a Myo10 mutant without the integrin-binding domain revealed that the ability of Myo10 to transport β1 integrins to the filopodia tip is required for invasion. Introduction of mutant p53 promoted Myo10 expression in cancer cells and pancreatic ductal adenocarcinoma in mice, whereas suppression of endogenous mutant p53 attenuated Myo10 levels and cell invasion. In clinical breast carcinomas, Myo10 was predominantly expressed at the invasive edges and correlated with the presence of TP53 mutations and poor prognosis. These data indicate that Myo10 upregulation in mutant p53–driven cancers is necessary for invasion and that plasma-membrane protrusions, such as filopodia, may serve as specialized metastatic engines.

Authors

Antti Arjonen, Riina Kaukonen, Elina Mattila, Pegah Rouhi, Gunilla Högnäs, Harri Sihto, Bryan W. Miller, Jennifer P. Morton, Elmar Bucher, Pekka Taimen, Reetta Virtakoivu, Yihai Cao, Owen J. Sansom, Heikki Joensuu, Johanna Ivaska

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Figure 6

Mutant p53 regulates Myo10 expression.

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Mutant p53 regulates Myo10 expression. (A) Western blot of Myo10, p53, a...
(A) Western blot of Myo10, p53, and actin (loading control) in the indicated cell lines. (B) Western blot of mutant p53–transfected (R175H or R273H) MCF-7 and in HCT-116 p53–/– cells stably expressing mutant p53 (R273H). The number of experiments (n) and the quantification of Myo10 levels relative to the control are shown. (C) PDAC sections from mice expressing mutant p53 (p53R172H) and mice with deleted p53 (p53flox) were stained and quantified (Slidepath software, pixel count) for Myo10 expression. Scale bar: 100 μm. (P = 0.047, Mann Whitney test, n = 5 tumors). (D) Early PanIN (top panels), late PanIN (middle panels), and PDAC (bottom panels) sections were stained for Myo10 and mutant p53 expression. Scale bars: 100 μm. (E) Western blotting of Myo10, p53, and tubulin in human pancreatic cancer cell lines. (F, G) Myo10 expression in MDA-MB-231 cells upon shRNA-mediated mutant p53 silencing and reexpression of shRNA-insensitive R175H p53 or WT p53 (mean ± SEM, n = 4, Mann Whitney test).