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PtdIns(3,4,5)P3-dependent Rac exchanger 1 (P-Rex1) promotes mammary tumor initiation and metastasis

Abstract

The Rac-GEF, P-Rex1, activates Rac1 signaling downstream of G protein-coupled receptors and PI3K. Increased P-Rex1 expression promotes melanoma progression; however, its role in breast cancer is complex, with differing reports of the effect of its expression on disease outcome. To address this we analyzed human databases, undertook gene array expression analysis, and generated unique murine models of P-Rex1 gain or loss of function. Analysis of PREX1 mRNA expression in breast cancer cDNA arrays and a METABRIC cohort revealed that higher PREX1 mRNA in ER(+ve)/luminal tumors was associated with poor outcome in luminal B cancers. Prex1 deletion in MMTV-neu or MMTV-PyMT mice reduced Rac1 activation in vivo and improved survival. High level MMTV-driven transgenic PREX1 expression resulted in apicobasal polarity defects and increased mammary epithelial cell proliferation associated with hyperplasia and development of de novo mammary tumors. MMTV-PREX1 expression in MMTV-neu mice increased tumor initiation and enhanced metastasis in vivo, but had no effect on primary tumor growth. Pharmacological inhibition of Rac1 or MEK1/2 reduced P-Rex1-driven tumoroid formation and cell invasion. Therefore, P-Rex1 can act as an oncogene and cooperate with HER2/neu to enhance breast cancer initiation and metastasis, despite having no effect on primary tumor growth.

Type Journal
ISBN 1091-6490 (Electronic) 0027-8424 (Linking)
Authors Srijakotre, N.; Liu, H. J.; Nobis, M.; Man, J.; Yip, H. Y. K.; Papa, A.; Abud, H. E.; Anderson, K. I.; Welch, H. C. E.; Tiganis, T.; Timpson, P.; McLean, C. A.; Ooms, L. M.; Mitchell, C. A.
Responsible Garvan Author Professor Paul Timpson
Publisher Name PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Published Date 2020-11-10
Published Volume 117
Published Issue 45
Published Pages 28056-28067
Status Published in-print
DOI 10.1073/pnas.2006445117
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/33097662