Abstract 2420: Loss of hCLCA4 promotes EMT in breast cancer

Abstract

Abstract The epithelial to mesenchymal transition (EMT) is a developmental program in which epithelial cells downregulate their cell-cell junctions, acquire spindle cell morphology and exhibit cellular motility. In breast cancer, EMT facilitates invasion of surrounding tissues and correlates closely with cancer metastasis and relapse. Previous studies in our lab showed that the candidate tumor suppressor hCLCA2 is expressed in differentiated, growth-arrested mammary epithelial cells but is downregulated during tumor progression and EMT. We further showed that hCLCA2 is a p53-inducible growth inhibitor whose loss indicates an increased risk of metastasis. Subsequent studies have revealed that another member of the CLCA gene family, hCLCA4, is also expressed in mammary epithelial levels, albeit at lower levels than hCLCA2. We find that hCLCA4 is also induced by stress and is similarly downregulated in breast cancer cell lines. Like hCLCA2, hCLCA4 is downregulated when EMT is induced by TGF beta, ectopic expression of mesenchymal transcription factors, or dilution of immortalized cells. Furthermore, knockdown of hCLCA4 in HMLE by shRNAs caused EMT. RNA and protein profiling for EMT markers showed that knockdown cells have lower expression epithelial marker E-cadherin and higher expression level of mesenchymal markers vimentin and fibronectin. Moreover, we found that hCLCA4 is co-regulated with hCLCA2 in HMLE cells. Knockdown of hCLCA2 led to down-regulation of hCLCA4 and vice versa. These findings suggest that hCLCA4 is, like hCLCA2, a marker of epithelial differentiation whose loss contributes to EMT and possibly metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2420. doi:1538-7445.AM2012-2420