RhoC disrupts tight junction formation and epithelial polarity in inflammatory breast cancer

MEI WU; ZHIFEN WU; CHIA-JEN LIU; ALEJANDRA C VENTURA; EILEEN L. WHITEMAN; BEN MARGOLIS; SOFIA D MERAJVER

San Diego, USA

Congreso; American Association for Cancer Research Annual Meeting 2008; 2008

American Association for Cancer Research

Inflammatory breast cancer (IBC) shows strong expression of E-cadherin. Unlike many other malignant breast cancers with low or null expression of E-cadherin, the mechanism of breast cell transformation into IBC remains poorly understood. Previous studies indicate that overexpression of RhoC GTPase is a specific genetic alteration in IBC tumors and in SUM149, an IBC cell line. We show here that knockdown of RhoC in SUM149 had no effect on the expression levels and the localization of E-cadherin. RhoC silencing, however, induced the formation of functional tight junctions (TJ), as evident by a sharp and continuous ZO-1 staining, correct co-localization of the TJ proteins and ZO-1, high transepithelial resistance, and the appearance of the TJ-like structure under transmission electron microscope. The restoration of TJ in RhoC-knockdown SUM149 cells is dependent on the expression of CRB3, a component in the CRB3/PALS1/PATJ polarity complex, in SUM149. Knockdown of a closely related isoform of RhoC, RhoA, failed to form TJ. Furthermore, knockdown of RhoC in SUM149 restored cell polarity by localizing the CRB3/PALS1/PATJ complex to TJ. In conclusion, RhoC GTPase activity disrupted epithelial polarity and proper formation of TJ to contribute to the epithelial-mesenchymal plasticity of SUM149.