ErbB-dependent P-Rex1/Rac activation leads to an increase in TGFbeta2 expression in breast cancer.

GONZÁLEZ, AGUSTÍN; GON, KARINA; BONAVÍA, EVANGELINA; PÉREZ, LOURDES; CUNEO, NICASIO; LARA, ÁNGELA; HORTON, GRACIELA; ARIAS, CLAUDIA; CORREA FERNANDO; KORDON, EDITH; WERTHEIMER, EVA; VORNETTI, SILVIA; SANCHOTENA, VERÓNICA; GARBOVESKY, CARLOS; ABBA, MARTÍN; FLAKS, DIEGO

Mar del Plata, Buenos Aires

Congreso; LXI Reunión de la Sociedad Argentina de Investigación Clínica (SAIC); 2016

Sociedad Argentina de Investigación Clinica

Due to the importance of breast cancer forArgentinianpublic health, it is essential to identify biomarkers of the local population which could improve early diagnosis, predict disease progression and provide guidelines for treatment with targeted therapies. P-Rex1, a Rac-GEF essential for ErbB-induced Rac activation and migration, is overexpressed in breast cancer. The activation of ErbB receptors modifies the expression of a large number of genes involved in breast cancer.Some of those genes are also regulated by P-Rex1. The aim of this work was to study the effect of HRG-triggered Rac activation on the expression of TGF2, which is also involved in cell migration, and to determine its dependence on P-Rex1. A time-course analysisof Rac1 activation induced with 10ng/ml HRG in T47D breast cancer cells (analyzed by Rac-activated pull down assays) revealed that the amount of activated Racincreases rapidly with a peak at 5 minutes and is maintained for at least one hour, followed by a gradual decrease at 6 h post-stimulation. Rac activation by HRG leads to an increase in TGF2mRNA levels, which is inhibited by P-Rex1 silencing (data obtained by cDNA microarray and quantitative PCR). Since breast cancer is a multifactorial disease and current therapies often fail to find the main focus that drives disease progression, our working hypothesis is that there is an interaction between different signaling pathways, which share a convergence node in P-Rex1/ Rac, and interact and synergize during breast cancer progression. Future experiments will determine whether activation of Rac depends on the convergence of the ErbB and TGF2pathways.In addition, we seek to determine the relevance of P-Rex1 in an Argentinean population of breast cancer patients. Weobserved that P-Rex1 mRNA levels in tumor samples are higher than in its concomitant adjacent tissue. These results confirm that these patients could be the focus of new therapies targeting P-Rex1 or its effectors.