ERBB-DEPENDENT P-REX1/RAC ACTIVATION LEADS TO AN INCREASE IN TGFβ2 EXPRESSION IN BREAST CANCER.

LARA, ANGELA; GOLZÁLEZ AGUSTÍN; PEREZ CUERVO L; MARTIN ABBA; KORDON EDITH; WERTHEIMER EVA

Congreso; LXI Reunión Anual SAIC; 2016

Due to the importance of breast cancer for Argentinian publichealth, it is essential to identify biomarkers of the local populationwhich could improve early diagnosis, predict disease progressionand provide guidelines for treatment with targeted therapies.P-Rex1, a Rac-GEF essential for ErbB-induced Rac activationand migration, is overexpressed in breast cancer. The activationof ErbB receptors modifies the expression of a large number ofgenes involved in breast cancer. Some of those genes are alsoregulated by P-Rex1. The aim of this work was to study the effectof HRG-triggered Rac activation on the expression of TGFb2,which is also involved in cell migration, and to determine its dependenceon P-Rex1. A time-course analysis of Rac1 activationinduced with 10 ng/ml HRG in T47D breast cancer cells (analyzedby Rac-activated pull down assays) revealed that the amount ofactivated Rac increases rapidly with a peak at 5 minutes and ismaintained for at least one hour, followed by a gradual decrease at6 h post-stimulation. Rac activation by HRG leads to an increase inTGFb2 mRNA levels, which is inhibited by P-Rex1 silencing (dataobtained by cDNA microarray and quantitative PCR). Since breastcancer is a multifactorial disease and current therapies often fail tofind the main focus that drives disease progression, our workinghypothesis is that there is an interaction between different signalingpathways, which share a convergence node in P-Rex1/ Rac, andinteract and synergize during breast cancer progression. Futureexperiments will determine whether activation of Rac depends onthe convergence of the ErbB and TGFb2 pathways. In addition, we seek to determine the relevance of P-Rex1 in an Argentineanpopulation of breast cancer patients. We observed that P-Rex1mRNA levels in tumor samples are higher than in its concomitantadjacent tissue. These results confirm that these patients couldbe the focus of new therapies targeting P-Rex1 or its effectors.