Abstract P1-07-12: Kaiso is a novel regulator of epithelial-to-mesenchymal transition in triple negative breast cancer cells

Abstract

Abstract Introduction: Breast cancer (BC) is the most frequent form of female cancer and a principal cause of female deaths worldwide. Most BC deaths are attributed to tumor metastasis to vital organs, and many studies have proposed a role for epithelial-to-mesenchymal transition (EMT) in BC metastasis especially the Triple Negative BC (TNBC) subtype. This theory is further strengthened by the observation that many triple-negative tumors display low E-cadherin expression, which is a hallmark of EMT. The TNBC subtype lack expression of the estrogen-receptor (ER), progesterone-receptor (PR) and human epidermal growth factor receptor-2, HER2. These tumors are highly aggressive with limited treatment options or targeted-therapies, and consequently TNBC patients have poor outcomes. Recently, increased nuclear expression of the transcription factor Kaiso was significantly correlated with high grade, BRCA1-related and basal/TNBCs. Kaiso is a novel transcription factor that we originally identified as a binding partner of p120-catenin (p120), a Src Kinase substrate and regulator of E-cadherin stability and turnover. Rationale and Research Objective: Though not much is known about the function of Kaiso in breast tumor progression and metastasis, Kaiso has been implicated in regulating E-cadherin expression, which raised the possibility that Kaiso might play a role in EMT. Thus we sought to elucidate the role of Kaiso in EMT and TNBC metastasis. Results: To achieve this goal, we created a stable Kaiso-depleted TNBC cell line (MDA-MB-231) to analyze the consequences of Kaiso-depletion on features attributed to metastasis, using immunoblot, wound healing and Matrigel invasion assays among other techniques. Interestingly, Kaiso-depletion led to reduced transcript and expression levels of the EMT markers Snail, Slug, ZEB1/2, TGFbRII, vimentin, and up-regulation of E-cadherin. Kaiso-depleted MDA-MB-231 cells also showed a gradual change in morphology from a mesenchymal to an epithelial phenotype referred to as mesenchymal to epithelial transition (MET). Loss of Kaiso further resulted in reduced cell motility and invasion. Ongoing studies seek to evaluate the effect of Kaiso-depletion on metastasis in vivo. Since there is evidence that the TGFβ signaling pathway drives EMT, and Kaiso-depletion resulted in reduced transcript levels of TGFβRII, future studies will determine if Kaiso plays a role in EMT/MET via promotion of the TGFβ signaling pathway. Overall Significance: Our study is the first to demonstrate a link between Kaiso and EMT/MET of TNBC cells and suggest that Kaiso may be a novel regulator of EMT in TNBC. Consequently, Kaiso might be useful as a therapeutic or prognostic tool in the treatment of TNBC. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-07-12.