Abstract 4384: Discovery of CD146/Latexin as a novel pathway suppressing breast tumor invasion.

CD146, also known as melanoma cell adhesion molecule or MUC18, was initially identified as a promoter of melanoma as well as prostate cancer progression and metastasis. Interestingly, however, CD146 appears to be a breast cancer (BC) tumor suppressor. The molecular mechanism of CD146 in cancer are still nascent and controversial. To address this discrepancy, we applied microarray gene expression profiling analysis, using a tetracycline (tet On)-inducible system of CD146 in the MDA-MB-231 BC cell line, and identified latexin (LXN) as a potential CD146-downstream signaling transcriptional target. LXN showed a 7 fold increase, which was confirmed in vitro by both time-course western blotting and RT-PCR analyses. In addition, NF-kappaB was identified as the molecular link between CD146 induction and LXN transactivation. More interestingly, we established the CD146-tet On inducible system in mouse BC xenograft model, and demonstrated that in vivo induction of CD146-inhibited breast tumor growth. Furthermore, breast tumor tissues from both Omani patients and patients from New Orleans area in Louisiana, were examined by immunohistochemistry for the expression of CD146 and LXN. Strikingly, the results revealed that the expression levels of both CD146 and its downstream target LXN showed parallel inhibition patterns in BC progression, with high expression in both normal and benign but low or no expression in malignant and metastatic breast tumor tissues. This study is the first to uncover a molecular link and provide evidence for a role of CD146/LXN-signaling in suppressing BC progression. Thus, reactivation of LXN through pharmacological manipulation holds particular promise for guiding the development of novel targeted-therapeutic strategies for BC. Citation Format: Allal Ouhtit, Zakariya Y. Abd Elmageed, Augusta Fernando, Rajiv Gaur, Ishita Gupta, Somya Shanmuganathan, Hamad Al-Riyami, Madhwa HG Raj. Discovery of CD146/Latexin as a novel pathway suppressing breast tumor invasion. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4384. doi:10.1158/1538-7445.AM2013-4384