CLCA2 Interactor EVA1 Is Required for Mammary Epithelial Cell Differentiation

Ramena, Grace; Yin, Yufang; Yu, Yang; Walia, Vijay; Elble, Randolph C.

doi:10.1371/journal.pone.0147489

Cited by 33 publications

(49 citation statements)

References 56 publications

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“…It is in accordance with the findings of others, and therefore tempting to speculate, that downregulation of mCLCA5 in the presence of cells expressing Stat3 activity reflects an invasive phenotype in these cells and potential epithelial–mesenchymal transition. 16, 22, 24 …”

Section: Discussionmentioning

confidence: 99%

“…CLCA proteins have been associated with diverse functions including cell adhesion, 16 apoptosis, tumourigenesis and mucus cell differentiation. 17 Of particular interest, both CLCA2 and CLCA4 have been shown to inhibit proliferation of breast cancer cells when ectopically expressed in vitro , 18 whereas normal breast tissue exhibits high levels of CLCA2 in both acini and small ducts.…”

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confidence: 99%

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Stat3 modulates chloride channel accessory protein expression in normal and neoplastic mammary tissue

et al. 2016

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Mammary gland regression at the cessation of lactation (involution) is an exquisitely orchestrated process of cell death and tissue remodelling in which Stat3 signalling has an essential role. The involution microenvironment of the mammary gland is considered to be pro-tumourigenic and a proportion of cases of pregnancy-associated breast cancer are suggested to originate in tandem with involution. However, the apparent paradox that STAT3 is required for cell death in normal mammary gland, but is associated with breast cancer cell survival, has not been resolved. Herein, we investigate Stat3-mediated regulation of expression of members of the calcium-activated chloride channel regulator (CLCA) family of proteins during involution and mammary carcinogenesis. Using the conditionally immortal mammary epithelial cell line KIM-2, together with mice exhibiting mammary epithelial cell-specific deletion of Stat3 during lactation, we demonstrate that expression of mCLCA1 and mCLCA2 is elevated in concert with activation of Stat3. By contrast, murine CLCA5 (mCLCA5), the murine orthologue of human CLCA2, is significantly upregulated at 24, 72 and 96 h of involution in Stat3 knockout mice, suggesting a reciprocal regulation of these proteins by Stat3 in vivo. Interestingly, orthotopic tumours arising from transplantation of 4T1 murine mammary tumour cells exhibit both phosphorylated Stat3 and mCLCA5 expression. However, we demonstrate that expression is highly compartmentalized to distinct subpopulations of cells, and that Stat3 retains a suppressive effect on mCLCA5 expression in 4T1 tumour cells. These findings enhance our understanding of the regulation of CLCA channel expression both in vitro and in vivo, and in particular, demonstrate that expression of mCLCA1 and mCLCA2 during involution is profoundly dependent upon Stat3, whereas the relationship between mCLCA5 and Stat3 activity is reciprocal and restricted to different subpopulations of cells.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Stat3 modulates chloride channel accessory protein expression in normal and neoplastic mammary tissue

et al. 2016

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“…CTBP1 plasmid and its control (pcDNA3) were described previously . pGL4 plasmids with different lengths of the CLCA2 promoter, pGIPZ.shCLCA2 and pGIPZ control, pLEX‐CLCA2 and pLEX were described previously …”

Section: Methodsmentioning

confidence: 99%

“…Previously, Elble group showed that CLCA2 is a negative regulator of proliferation and epithelial–mesenchymal transition (EMT) in breast cancer (BrCa) . Recently, they reported that CLCA2 is part of two functional adhesion complexes, one with epithelial V‐like antigen 1 (EVA1) and zona occludens 1 (ZO‐1), and the other with β‐catenin (CTNNB1), that are involved in EMT suppression . Also BrCa patients with low CLCA2 expression in primary tumors have more metastasis .…”

Section: Introductionmentioning

confidence: 99%

CLCA2 epigenetic regulation by CTBP1, HDACs, ZEB1, EP300 and miR‐196b‐5p impacts prostate cancer cell adhesion and EMT in metabolic syndrome disease

Porretti

Dalton

Massillo

et al. 2018

Intl Journal of Cancer

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Prostate cancer (PCa) is the most common cancer among men. Metabolic syndrome (MeS) is associated with increased PCa aggressiveness and recurrence. Previously, we proposed C-terminal binding protein 1 (CTBP1), a transcriptional co-repressor, as a molecular link between these two conditions. Notably, CTBP1 depletion decreased PCa growth in MeS mice. The aim of this study was to investigate the molecular mechanisms that explain the link between MeS and PCa mediated by CTBP1. We found that CTBP1 repressed chloride channel accessory 2 (CLCA2) expression in prostate xenografts developed in MeS animals. CTBP1 bound to CLCA2 promoter and repressed its transcription and promoter activity in PCa cell lines. Furthermore, we found that CTBP1 formed a repressor complex with ZEB1, EP300 and HDACs that modulates the CLCA2 promoter activity. CLCA2 promoted PCa cell adhesion inhibiting epithelial-mesenchymal transition (EMT) and activating CTNNB1 together with epithelial marker (CDH1) induction, and mesenchymal markers (SNAI2 and TWIST1) repression. Moreover, CLCA2 depletion in PCa cells injected subcutaneously in MeS mice increased the circulating tumor cells foci compared to control. A microRNA (miRNA) expression microarray from PCa xenografts developed in MeS mice, showed 21 miRNAs modulated by CTBP1 involved in angiogenesis, extracellular matrix organization, focal adhesion and adherents junctions, among others. We found that miR-196b-5p directly targets CLCA2 by cloning CLCA2 3'UTR and performing reporter assays. Altogether, we identified a new molecular mechanism to explain PCa and MeS link based on CLCA2 repression by CTBP1 and miR-196b-5p molecules that might act as key factors in the progression onset of this disease.

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“…Knockdown of CLCA2 or CLCA4 is sufficient in HMLE cells to induce the expression of the mesenchymal marker vimentin and supress the epithelial marker E-Cadherin (Walia et al 2012, Yu et al 2013). In the case of CLCA2, the regulation of EMT may at least in part be through interactions with the cell junctional protein EVA1 (Ramena et al 2016). Future studies are now required to define the relative importance in changes in chloride flux in these events, and the ability of the loss of CLCA2 or CLCA4 to induce a mesenchymal phenotype in other models of EMT, including those not of breast cancer origin.…”

Section: Chloride Channels and Emt In Cancer Cellsmentioning

confidence: 99%

Plasma membrane ion channels and epithelial to mesenchymal transition in cancer cells

Azimi¹,

Monteith²

2016

Endocrine-Related Cancer

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A variety of studies have suggested that epithelial to mesenchymal transition (EMT) may be important in the progression of cancer in patients through metastasis and/or therapeutic resistance. A number of pathways have been investigated in EMT in cancer cells. Recently, changes in plasma membrane ion channel expression as a consequence of EMT have been reported. Other studies have identified specific ion channels able to regulate aspects of EMT induction. The utility of plasma membrane ion channels as targets for pharmacological modulation make them attractive for therapeutic approaches to target EMT. In this review, we provide an overview of some of the key plasma membrane ion channel types and highlight some of the studies that are beginning to define changes in plasma membrane ion channels as a consequence of EMT and also their possible roles in EMT induction.

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CLCA2 Interactor EVA1 Is Required for Mammary Epithelial Cell Differentiation

Cited by 33 publications

References 56 publications

Stat3 modulates chloride channel accessory protein expression in normal and neoplastic mammary tissue

Stat3 modulates chloride channel accessory protein expression in normal and neoplastic mammary tissue

CLCA2 epigenetic regulation by CTBP1, HDACs, ZEB1, EP300 and miR‐196b‐5p impacts prostate cancer cell adhesion and EMT in metabolic syndrome disease

Plasma membrane ion channels and epithelial to mesenchymal transition in cancer cells

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