Mislocalization of the cell polarity protein Scribble promotes mammary tumorigenesis and is associated with basal breast cancer

Feigin, M. E., Akshinthala, S. D., Araki, K., Rosenberg, A. Z., Muthuswamy, L. B., Martin, B., Lehmann, B. D., Berman, H. K., Pietenpol, J. A., Cardiff, R. D., Muthuswamy, S. K. (March 2014) Mislocalization of the cell polarity protein Scribble promotes mammary tumorigenesis and is associated with basal breast cancer. Cancer Research, 74 (11). pp. 3180-3194. ISSN 0008-5472

URL: http://www.ncbi.nlm.nih.gov/pubmed/24662921
DOI: 10.1158/0008-5472.can-13-3415

Abstract

Scribble (SCRIB) localizes to cell-cell junctions and regulates establishment of epithelial cell polarity. Loss of expression of SCRIB functions as a tumor suppressor in Drosophila and mammals, conversely, overexpression of SCRIB promotes epithelial differentiation in mammals. Here, we report that SCRIB is frequently amplified, mRNA over-expressed and protein is mislocalized from cell-cell junctions in human breast cancers. High levels of SCRIB mRNA are associated with poor clinical prognosis identifying an unexpected role for SCRIB in breast cancer. We find that, transgenic mice expressing a SCRIB mutant (Pro 305 to Leu (P305L)) that fails to localize to cell-cell junctions, under the control of the mouse mammary tumor virus long terminal repeat promoter, develop multifocal hyperplasia that progresses to highly pleomorphic and poorly differentiated tumors with basal characteristics. SCRIB interacts with PTEN and the expression of P305L, but not wild-type SCRIB, promotes an increase in PTEN levels in the cytosol. Overexpression of P305L, but not wild type SCRIB, activates the Akt/mTOR/S6K signaling pathway. Human breast tumors overexpressing SCRIB have high levels of S6K but do not harbor mutations in PTEN or PIK3CA, identifying SCRIB amplification as a mechanism of activating PI3K signaling in tumors without mutations in PIK3CA or PTEN. Thus, we demonstrate that high levels of mislocalized SCRIB functions as a neomorph to promote mammary tumorigenesis by affecting subcellular localization of PTEN and activating an Akt/mTOR/S6kinase signaling pathway.

Item Type: Paper
Subjects: organs, tissues, organelles, cell types and functions > organs types and functions > breast
diseases & disorders > cancer > cancer types > breast cancer
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell polarity
CSHL Authors:
Communities: CSHL labs > Muthuswamy lab
CSHL Cancer Center Program > Signal Transduction
Depositing User: Matt Covey
Date: 24 March 2014
Date Deposited: 28 Mar 2014 19:26
Last Modified: 16 Oct 2015 13:57
Related URLs:
URI: http://repository.cshl.edu/id/eprint/29729

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