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

Michael E. Feigin, S. Dipikaa Akshinthala, Kiyomi Araki, Avi Z. Rosenberg, Lakshmi B. Muthuswamy, Bernard Martin, Brian D. Lehmann, Hal K. Berman, Jennifer A. Pietenpol, Robert Cardiff, Senthil K. Muthuswamy

Research output: Contribution to journalArticle

58 Citations (Scopus)

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 overexpressed, 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 phosphatase and tensin homolog (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.

Original languageEnglish (US)
Pages (from-to)3180-3194
Number of pages15
JournalCancer Research
Volume74
Issue number11
DOIs
StatePublished - Jun 1 2014

Fingerprint

Cell Polarity
Phosphoric Monoester Hydrolases
Carcinogenesis
Breast
Intercellular Junctions
Breast Neoplasms
Proteins
Mammals
Mouse mammary tumor virus
Neoplasms
Messenger RNA
Mutation
Terminal Repeat Sequences
Phosphatidylinositol 3-Kinases
Cytosol
Transgenic Mice
Drosophila
Hyperplasia
Epithelial Cells
Tensins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Feigin, M. E., Akshinthala, S. D., Araki, K., Rosenberg, A. Z., Muthuswamy, L. B., Martin, B., ... Muthuswamy, S. K. (2014). Mislocalization of the cell polarity protein scribble promotes mammary tumorigenesis and is associated with basal breast cancer. Cancer Research, 74(11), 3180-3194. https://doi.org/10.1158/0008-5472.CAN-13-3415

Mislocalization of the cell polarity protein scribble promotes mammary tumorigenesis and is associated with basal breast cancer. / Feigin, Michael E.; Akshinthala, S. Dipikaa; Araki, Kiyomi; Rosenberg, Avi Z.; Muthuswamy, Lakshmi B.; Martin, Bernard; Lehmann, Brian D.; Berman, Hal K.; Pietenpol, Jennifer A.; Cardiff, Robert; Muthuswamy, Senthil K.

In: Cancer Research, Vol. 74, No. 11, 01.06.2014, p. 3180-3194.

Research output: Contribution to journalArticle

Feigin, ME, Akshinthala, SD, Araki, K, Rosenberg, AZ, Muthuswamy, LB, Martin, B, Lehmann, BD, Berman, HK, Pietenpol, JA, Cardiff, R & Muthuswamy, SK 2014, 'Mislocalization of the cell polarity protein scribble promotes mammary tumorigenesis and is associated with basal breast cancer', Cancer Research, vol. 74, no. 11, pp. 3180-3194. https://doi.org/10.1158/0008-5472.CAN-13-3415
Feigin, Michael E. ; Akshinthala, S. Dipikaa ; Araki, Kiyomi ; Rosenberg, Avi Z. ; Muthuswamy, Lakshmi B. ; Martin, Bernard ; Lehmann, Brian D. ; Berman, Hal K. ; Pietenpol, Jennifer A. ; Cardiff, Robert ; Muthuswamy, Senthil K. / Mislocalization of the cell polarity protein scribble promotes mammary tumorigenesis and is associated with basal breast cancer. In: Cancer Research. 2014 ; Vol. 74, No. 11. pp. 3180-3194.
@article{00b7a07115ca4455b58a4172b0548bb4,
title = "Mislocalization of the cell polarity protein scribble promotes mammary tumorigenesis and is associated with basal breast cancer",
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 overexpressed, 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 phosphatase and tensin homolog (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.",
author = "Feigin, {Michael E.} and Akshinthala, {S. Dipikaa} and Kiyomi Araki and Rosenberg, {Avi Z.} and Muthuswamy, {Lakshmi B.} and Bernard Martin and Lehmann, {Brian D.} and Berman, {Hal K.} and Pietenpol, {Jennifer A.} and Robert Cardiff and Muthuswamy, {Senthil K.}",
year = "2014",
month = "6",
day = "1",
doi = "10.1158/0008-5472.CAN-13-3415",
language = "English (US)",
volume = "74",
pages = "3180--3194",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "11",

}

TY - JOUR

T1 - Mislocalization of the cell polarity protein scribble promotes mammary tumorigenesis and is associated with basal breast cancer

AU - Feigin, Michael E.

AU - Akshinthala, S. Dipikaa

AU - Araki, Kiyomi

AU - Rosenberg, Avi Z.

AU - Muthuswamy, Lakshmi B.

AU - Martin, Bernard

AU - Lehmann, Brian D.

AU - Berman, Hal K.

AU - Pietenpol, Jennifer A.

AU - Cardiff, Robert

AU - Muthuswamy, Senthil K.

PY - 2014/6/1

Y1 - 2014/6/1

N2 - 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 overexpressed, 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 phosphatase and tensin homolog (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.

AB - 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 overexpressed, 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 phosphatase and tensin homolog (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.

UR - http://www.scopus.com/inward/record.url?scp=84902176984&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84902176984&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-13-3415

DO - 10.1158/0008-5472.CAN-13-3415

M3 - Article

C2 - 24662921

AN - SCOPUS:84902176984

VL - 74

SP - 3180

EP - 3194

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 11

ER -