Connexin46 Expression Enhances Cancer Stem Cell and Epithelial-to-Mesenchymal Transition Characteristics of Human Breast Cancer MCF-7 Cells

Abstract

Connexins (Cxs) are a family of proteins that form two different types of ion channels: hemichannels and gap junction channels. These channels participate in cellular communication, enabling them to share information and act as a synchronized syncytium. This cellular communication has been considered a strong tumor suppressor, but it is now recognized that some type of Cxs can be pro-tumorigenic. For example, Cx46 expression is increased in human breast cancer samples and correlates with cancer stem cell (CSC) characteristics in human glioma. Thus, we explored whether Cx46 and glioma cells, can set up CSC and epithelial-to-mesenchymal transition (EMT) properties in a breast cancer cell line. To this end, we transfected MCF-7 cells with Cx46 attached to a green fluorescent protein (Cx46GFP), and we determined how its expression orchestrates both the gene-expression and functional changes associated with CSC and EMT. We observed that Cx46GFP increased Sox2, Nanog, and OCT4 mRNA levels associated with a high capacity to form monoclonal colonies and tumorspheres. Similarly, Cx46GFP increased the mRNA levels of n-cadherin, Vimentin, Snail and Zeb1 to a higher migratory and invasive capacity. Furthermore, Cx46GFP transfected in MCF-7 cells induced the release of higher amounts of VEGF, which promoted angiogenesis in HUVEC cells. We demonstrated for the first time that Cx46 modulates CSC and EMT properties in breast cancer cells and thus could be relevant in the design of future cancer therapies.

Connexins and angiogenesis: Functional aspects, pathogenesis, and emerging therapies (Review)

“…4 ). Cx46 regulates cancer stem cell and epithelial-to-mesenchymal transition features in breast cancer cells, suggesting that it may be useful in the development of future cancer therapeutics ( 59 ).…”

Mechanisms of Cell Adhesion Molecules in Endocrine-Related Cancers: A Concise Outlook

“…Decreased CDH1 expression is significantly correlated with a higher-grade, triple-negative receptor status, and poor prognosis in invasive breast carcinoma ( 89 ). Upregulation of cyclin D1, β-catenin, N-cadherin, MMP-2, MMP-9, and ICAM-1 and downregulation of CDH1 were found in doxorubicin-resistant TNBC cells ( 90 ). CDH1 is crucial for epithelial polarization and differentiation.…”

“…Moreover, taxane therapy resistance was related to reduced PRP4K expression, depletion of PRP4K in TNBC cells (MDA-MB-231), and enhanced 2D migration, and 3D invasion correlated with higher fibronectin levels rather than changes in CDH1 ( 114 ). Connexins linked to N-cadherin, vimentin, Snail, and Zeb1 modulate CSC and EMT properties in breast cancer cells ( 90 ).…”

A Quantitative Assay for Ca2+ Uptake through Normal and Pathological Hemichannels

“…We focused on Cx26, which is expressed at extremely low, oftentimes undetectable levels in epidermal keratinocytes, yet, paradoxically, mutant Cx26 leaky/hyperactive HCs cause genodermatoses, including keratitis-ichthyosis-deafness syndrome (KID) and palmoplantar keratoderma with deafness (PPKDFN) that may drastically compromise quality of life and life-long health [40,51,52] (Table 1). To broaden the impact of this study and demonstrate the wider applicability of the methodology, we also investigated HCs composed of Cx46 [11,12], which is an important target for cancer therapy [53][54][55][56][57] and, when mutated, is involved in cataract formation [58].…”