68P - The interplay between the cell adhesion molecules CD44 and CD146 in breast cancer metastasis
|Date||08 May 2014|
|Session||Welcome reception and Poster Walk|
|Topics|| Breast Cancer, Metastatic
|Citation||Annals of Oncology (2014) 25 (suppl_1): i23-i24. 10.1093/annonc/mdu070|
I. Gupta, M.E. Abdraboh, A.D. Hollenbach, S. Shanmuganathan, H. Al-Riyami, M. Raj, A. Ouhtit
Cancer cell metastasis is one of the most critical steps in tumor development and is responsible for more than 80 of cancer related deaths. Among the molecules involved in promoting cancer metastasis, the role of the cell adhesion molecules, CD44 and CD146 are well known in promoting cancer cell motility and metastasis. Despite this knowledge, the molecular mechanism through which CD44 promotes tumor development and cell metastasis is still nascent. CD146 (MUC 18) was, first identified in highly metastatic melanomas. The absence of CD146 in normal melanocytes and its high expression in melanomas suggests its tumor promoting actions. Despite the association between CD146 expression and development of melanoma, its expression patterns and role in normal and metastatic breast tissues still remains controversial. This study aims to elucidate some of these discrepancies by presenting CD146 as a downstream target for CD44, in a way such that CD146 expression is related to CD44 and regulates the tumor microenvironment. To test this hypothesis, MCF7-B5 and MCF7-B5-CD146 cell lines were treated in the presence and absence of dox which were validated by Western blotting and immunofluorescence. Upon the inducible expression and activation of CD44, we observed a substantial decrease in the expression of cellular CD146 with an equally notable converse effect upon siRNA inhibition of CD44 expression. We further, observed an inverse relationship between CD44 and CD146 in late stage breast adenocarcinoma tissue samples relative to the adjacent normal tissue, validating our in-vitro studies. Stimulation of CD44 expression led to a decrease in cellular CD146 and an increase in soluble CD146 suggesting that the CD44 activation of MMP activity results in the cleavage of CD146 from the surface of the cell. Finally, inhibiting CD146 resulted in breast cancer cell invasiveness, suggesting that loss of cell surface CD146 is required for the promotion of breast cancer invasiveness. This study demonstrates that CD44 signaling contributes to cellular expression of CD146, which subsequently can lead to breast cancer invasiveness.
All authors have declared no conflicts of interest.