Abstract
BackgroundDespite recent advances in the diagnosis and treatment of breast cancer, metastasis remains the main cause of death. Since migration of tumor cells is considered a prerequisite for tumor cell invasion and metastasis, a pressing goal in tumor biology has been to elucidate factors regulating their migratory activity. Protein kinase C alpha (PKCα) is a serine-threonine protein kinase implicated in cancer metastasis and associated with poor prognosis in breast cancer patients. In this study, we set out to define the signaling axis mediated by PKCα to promote breast cancer cell migration.MethodsOncomine™ overexpression analysis was used to probe for PRKCA (PKCα) and FOXC2 expression in mRNA datasets. The heat map of PRKCA, FOXC2, and CTNND1 were obtained from the UC Santa Cruz platform. Survival data were obtained by PROGgene and available at http://www.compbio.iupui.edu/proggene. Markers for EMT and adherens junction were assessed by Western blotting and quantitative polymerase chain reaction. Effects of PKCα and FOXC2 on migration and invasion were assessed in vitro by transwell migration and invasion assays respectively. Cellular localization of E-cadherin and p120-catenin was determined by immunofluorescent staining. Promoter activity of p120-catenin was determined by dual luciferase assay using a previously validated p120-catenin reporter construct. Interaction between FOXC2 and p120-catenin promoter was verified by chromatin immunoprecipitation assay.ResultsWe determined that PKCα expression is necessary to maintain the migratory and invasive phenotype of both endocrine resistant and triple negative breast cancer cell lines. FOXC2 acts as a transcriptional repressor downstream of PKCα, and represses p120-catenin expression. Consequently, loss of p120-catenin leads to destabilization of E-cadherin at the adherens junction. Inhibition of either PKCα or FOXC2 is sufficient to rescue p120-catenin expression and trigger relocalization of p120-catenin and E-cadherin to the cell membrane, resulting in reduced tumor cell migration and invasion.ConclusionsTaken together, these results suggest that breast cancer metastasis may partially be controlled through PKCα/FOXC2-dependent repression of p120-catenin and highlight the potential for PKCα signal transduction networks to be targeted for the treatment of endocrine resistant and triple negative breast cancer.
Highlights
Despite recent advances in the diagnosis and treatment of breast cancer, metastasis remains the main cause of death
triple negative breast cancer (TNBC) tumors display high expression of Protein kinase C alpha (PKCα) and FOXC2, and low expression of p120-catenin To investigate the relationship between PKCα, FOXC2 and p120-catenin, we first examined the OncomineTM database for relative transcript levels of PRKCA and FOXC2
Whereas FOXC2 was previously demonstrated to be a repressor of p120-catenin expression in lung cancer [20], it is not known whether this inverse relationship holds true in breast cancer
Summary
Despite recent advances in the diagnosis and treatment of breast cancer, metastasis remains the main cause of death. Factors that regulate p120-catenin can influence the stability of E-cadherin and AJs respectively One of these factors is FOXC2, a forkhead transcription factor that actively represses p120-catenin transcription in nonsmall cell lung cancer (NSCLC) cell lines [20]. Expression of FOXC2 is associated with and causal to chemotherapy resistance and metastasis in triple negative breast cancer (TNBC) [21, 22], a subtype defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression It remains unknown whether FOXC2 can actively repress transcription of p120-catenin in breast cancer
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