Oncotarget

Research Papers:

Loss of Tpm4.1 leads to disruption of cell-cell adhesions and invasive behavior in breast epithelial cells via increased Rac1 signaling

SukYeong Jeong, SunYoung Lim, Galina Schevzov, Peter W. Gunning and David M. Helfman _

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Oncotarget. 2017; 8:33544-33559. https://doi.org/10.18632/oncotarget.16825

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Abstract

SukYeong Jeong1, SunYoung Lim1, Galina Schevzov2, Peter W. Gunning2, David M. Helfman1

1Department of Biological Sciences, Korean Advanced Institute of Science and Technology, Daejeon, Republic of Korea

2Oncology Research Unit, School of Medical Sciences, UNSW Australia, Sydney, NSW, Australia

Correspondence to:

David M. Helfman, email: dhelfman@kaist.ac.kr

Keywords: tropomyosin, TPM4, migration, invasion, cell adhesions

Received: December 14, 2016     Accepted: March 22, 2017     Published: April 04, 2017

ABSTRACT

Here we report the identification and characterization of a novel high molecular weight isoform of tropomyosin, Tpm4.1, expressed from the human TPM4 gene. Tpm4.1 expression is down-regulated in a subset of breast cancer cells compared with untransformed MCF10A breast epithelial cells and in highly metastatic breast cancer cell lines derived from poorly metastatic MDA-MD-231 cells. In addition, patients with invasive ductal breast carcinoma show decreased TPM4 expression compared with patients with ductal breast carcinoma in situ, and low TPM4 expression is associated with poor prognosis. Loss of Tpm4.1 using siRNA in MCF10A cells increases cell migration in wound-healing and Boyden chamber assays and invasion out of spheroids as well as disruption of cell-cell adhesions. Down-regulation of Tpm4.1 in MDA-MB-231 cells leads to disruption of actin organization and increased cell invasion and dissemination from spheroids into collagen gels. The down-regulation of Tpm4.1 induces Rac1-mediated alteration of myosin IIB localization, and pharmacologic inhibition of Rac1 or down-regulation of myosin IIB using siRNA inhibits the invasive phenotypes in MCF10A cells. Thus Tpm4.1 plays an important role in blocking invasive behaviors through Rac1-myosin IIB signaling and our findings suggest that decreased expression of Tpm4.1 might play a crucial role during tumor progression.


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