Abstract P3-05-09: The role of TGF-beta receptor type 3 in breast cancer progression

Abstract

Abstract Breast cancer is a diverse group of diseases. Gene expression profiling has identified luminal A, luminal B, Her2-like, Normal breast-like and Basal-like as major classifications of breast cancer diseases. These correlate to the overall patient survival with the basal-like subtype, clinically termed as triple-negative breast cancers (TNBC), demonstrating the poorest overall outcome. The poor patient outcome is primarily due to absence of hormonal receptor targets ER, PR and HER2 which are the major drug-targets for currently available therapies. Considering that TNBC lacks well-defined molecular targets, our group pursued extensive genomic molecular and biological analysis of over 500 tumor tissues from TNBC patients. Ultimately, this led to the discovery of six, TNBC subtypes; among which are Mesenchymal-Stem Like (MSL) and Mesechymal (M). These two subtypes share a unique biological driver, the TGF-beta pathway. To gain insight into the role of the TGF-β pathway signaling in TNBC we have performed gene expression analysis on all six TNBC subtypes. A major finding was that among all TGF-β pathway-associated genes, TGF-beta receptor type 3 (TBR3) is most differentially expressed in MSL and M tumor subtypes of TNBC. Based on these findings, we are hypothesizing that TBR3 is required for maintenance of tumorigenicity in MSL and M subtypes of the triple-negative breast cancer. In order to test our hypothesis we have screened 15 TNBC cell lines for both RNA and protein levels of TBR3 and validated that TBR3 is differentially expressed in M and MSL subtypes. Furthermore, we have manipulated TBR3 expression in M and MSL TNBC cell lines and tested their ‘biologies’ using both an in vitro and in vivo model systems. Preliminary results indicate that upon silencing TBR3 expression, cell motility as well as ability to cluster together in 3D culture system is significantly changed. In addition, our xenograft mouse model also demonstrated a significant change in tumor onset and growth. We are interested in validating the prognostic and functional contribution of TBR3 to the breast cancer progression. The results of this study will provide insight into the potential use of the TGF-β signaling axis for prognostic or therapeutic utility in breast cancer patients. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-05-09.