Abstract
Abstract Loss of E-cadherin, a core member of the epithelial adherens junction (AJ), leads to the induction of the epithelial-mesenchymal transition (EMT), a phenomenon where epithelial cells de-differentiate towards a more motile and invasive mesenchymal cell type. Because of its stabilizing function in the AJ, p120-catenin has caught attention in the context of tumor development and progression. We previously reported that expression of protein kinase C alpha (PKCα) imparts a hormone-independent, and tamoxifen-resistant phenotype in T47D:A18/PKCα breast cancer cells. Our preliminary data strongly indicate a positive relationship between PKCα and FOXC2, a forkhead transcription factor shown to be a central mediator of the EMT program and tumor metastasis. Data mining from Oncomine database revealed a strong correlation between PRKCA and FOXC2 in basal A triple negative breast cancer (TNBC) cell lines. In this study, two representative cell lines, HCC1937 and HCC1143, were chosen to investigate the relationship between PKCα, FOXC2, and p120-catenin, and how their interplay alters migration and invasion of TNBC and endocrine resistant breast cancer. Cell lines (T47D:A18/PKCα, HCC1143, HCC1937) were maintained as previously described and according to ATCC guidelines. Expression of PKCα and FOXC2 were manipulated using siRNA targeting PKCα and FOXC2 respectively. Transcripts level of FOXC2 (FOXC2) and CTNND1(p120-catenin) were measured using quantitative PCR. PKCα, FOXC2, and p120-catenin protein expression was measured by Western blot using PKCα (GE-Healthcare, 1:200), FOXC2 (Abcam, 1:500), and p120-catenin (Cell Signaling, 1:500) antibodies respectively. All three cell lines were found to co-express high level of PKCα and FOXC2. Knockdown of PKCα resulted in a down-regulation of FOXC2 transcripts and protein. However, knockdown of FOXC2 did not alter expression of PKCα, indicating PKCα is an upstream regulator of FOXC2, and not vice versa. Downregulation of either PKCα or FOXC2 led to a rescue of p120-catenin, and not E-cadherin, transcripts. Re-expression of p120-catenin transcripts also resulted in re-expression of the protein. Knockdown of FOXC2 in T47D:A18/ PKCα cells led to a significant reduction in migratory and invasive potential of these cells, to the same extent as knockdown of PKCα For the first time, we are reporting PKCα as a novel regulator of FOXC2 in TNBC and endocrine-resistant breast cancer. We also identified p120-catenin as a potential target of PKCα and FOXC2. Down-regulation of p120-catenin by either PKCα or FOXC2 may be a critical event in the dissolution of the AJ, which facilitates migration of breast cancer cells. Citation Format: Thao ND Pham, Bethany Perez-White, Debra A. Tonetti. Protein kinase C alpha (PKCα) is a novel regulator of FOXC2 and p120-catenin in triple negative and endocrine resistant breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4095. doi:10.1158/1538-7445.AM2015-4095
Published Version
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