Characterization of a P-Rex1 gene signature in breast cancer cells.

Laura Barrio-Real,Eva Wertheimer,Martin C Abba,Marcelo G Kazanietz,Rachana Garg

doi:10.18632/oncotarget.10285

Laura Barrio-Real, Eva Wertheimer + Show 3 more

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https://doi.org/10.18632/oncotarget.10285

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Abstract

The Rac nucleotide Exchange Factor (Rac-GEF) P-Rex1 is highly expressed in breast cancer, specifically in the luminal subtype, and is an essential mediator of actin cytoskeleton reorganization and cell migratory responses induced by stimulation of ErbB and other tyrosine-kinase receptors. Heregulin (HRG), a growth factor highly expressed in mammary tumors, causes the activation of P-Rex1 and Rac1 in breast cancer cells via ErbB3, leading to a motile response. Since there is limited information about P-Rex1 downstream effectors, we carried out a microarray analysis to identify genes regulated by this Rac-GEF after stimulation of ErbB3 with HRG. In T-47D breast cancer cells, HRG treatment caused major changes in gene expression, including genes associated with motility, adhesion, invasiveness and metastasis. Silencing P-Rex1 expression from T-47D cells using RNAi altered the induction and repression of a subset of HRG-regulated genes, among them genes associated with extracellular matrix organization, migration, and chemotaxis. HRG induction of MMP10 (matrix metalloproteinase 10) was found to be highly sensitive both to P-Rex1 depletion and inhibition of Rac1 function by the GTPase Activating Protein (GAP) β2-chimaerin, suggesting the dependence of the P-Rex1/Rac1 pathway for the induction of genes critical for breast cancer invasiveness. Notably, there is a significant association in the expression of P-Rex1 and MMP10 in human luminal breast cancer, and their co-expression is indicative of poor prognosis.

Highlights

Rho GTPases represent a key family within the superfamily of Ras-related small G-proteins that plays fundamental roles in biology and disease
The highest inductions were for GLIPR1 (~30-fold), a gene hormonally-regulated in breast cancer cells [34], and SYTL2 (~12-fold), a trafficking protein known as Breast Cancer-Associated antigen SGA-72M [35]
Studies from our group and others reported that P-Rex1, a Rac nucleotide Exchange Factor (Rac-GEF) originally discovered in neutrophils [16], is highly expressed in a subset of breast cancers, in the luminal subtype, and that its expression is associated with the development of breast cancer metastasis [15, 19]

Summary

Introduction

Rho GTPases represent a key family within the superfamily of Ras-related small G-proteins that plays fundamental roles in biology and disease. Rac activity is tightly regulated by guanine nucleotide exchange factors (Rac-GEFs), which activate Rac by promoting the exchange of GDP by GTP, and GTPase-activating proteins (GAPs) that accelerate Rac intrinsic GTPase activity, leading to its inactivation [1,2,3]. Gain-of-function mutations in Rac and a constitutively active splice variant (Rac 1b) have been found in a number of cancer types [4,5,6,7], hyperactivation of Rac is for the most part associated with aberrant overexpression or hyperactivation of Rac-GEFs [8,9,10,11]. Rac hyperactive status leads to enhanced activation of downstream effectors such as Pak and the www.impactjournals.com/oncotarget consequent elevated migratory and invasive capacity of cancer cells, favoring metastatic dissemination [11,12,13,14]

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