66P - CD146 suppresses breast tumor invasion via its novel downstream transcriptional target gene, TimpV

Date 08 May 2014
Event IMPAKT 2014
Session Welcome reception and Poster Walk
Topics Breast Cancer
Pathology/Molecular Biology
Presenter Allal Ouhtit
Citation Annals of Oncology (2014) 25 (suppl_1): i23-i24. 10.1093/annonc/mdu070
Authors A. Ouhtit, I. Gupta, A. Fernando, R. Gaur, S. Shanmuganathan, H. Al-Riyami, M. Raj
  • Department Of Genetics, College of Medicine and Health Sciences, Sultan Qaboos University, Al Khoud - Muscat/OM

Abstract

CD146, a marker of endothelial cells, promotes tumor progression of many cancers including melanoma and the prostate. Strikingly, several lines of evidence suggest that it is a suppressor of breast cancer (BC) progression. In addition, not only the ligand(s) has not been identified, but CD146-downstream mechanisms remain unknown. Here, we report a novel molecular mechanism by which CD146 acts as a suppressor of breast tumor growth. A novel transcriptional target of CD146-suppressed BC, TimpV, the only endogenous protein inhibitor known for metallocarboxypeptidases, was identified and validated using novel validated Enhanced Green Fluorescent Protein (EGFP)-inducible systems of CD146 expression in both, the weakly and the highly invasive BC cell lines MCF-7 and MDA-MB-231, respectively. CD146/TimpV association was validated by quantitative PCR and immunoblotting experiments in a range of BC cells. In functional experiments, both CD146 induction and siRNA experimental approaches revealed that, while TimpV is positively regulated by CD146 to suppress BC invasion, it is negatively regulated in melanoma cells, where increased CD146 inhibits TimpV to promote melanoma cell motility. Furthermore, the functional relevance of TimpV to CD146-suppressed BC cell invasion and metastasis was demonstrated using both, in-vitro models through selective RNAi-suppression of TimpV in the CD146-expressing BC inducible cells, as well as in-vivo using EGFP-inducible CD146 expression in xenograft mouse models. Our study is the first to provide a functional molecular link of TimpV to cancer via a unique axis that underpin CD146-suppressed BC metastasis, thus identifying TimpV as a potential target for guiding the development of novel rational therapeutic strategies against BC.

Disclosure:

All auhors have declared no conflicts of interest.