Abstract
(1) Background: The expression of connexin 43 (Cx43) is disrupted in breast cancer, and re-expression of this protein in human breast cancer cell lines leads to decreased proliferation and invasiveness, suggesting a tumor suppressive role. This study aims to investigate the role of Cx43 in proliferation and invasion starting from non-neoplastic breast epithelium. (2) Methods: Nontumorigenic human mammary epithelial HMT-3522 S1 cells and Cx43 shRNA-transfected counterparts were cultured under 2-dimensional (2-D) and 3-D conditions. (3) Results: Silencing Cx43 induced mislocalization of β-catenin and Scrib from apicolateral membrane domains in glandular structures or acini formed in 3-D culture, suggesting the loss of apical polarity. Cell cycle entry and proliferation were enhanced, concomitantly with c-Myc and cyclin D1 upregulation, while no detectable activation of Wnt/β-catenin signaling was observed. Motility and invasion were also triggered and were associated with altered acinar morphology and activation of ERK1/2 and Rho GTPase signaling, which acts downstream of the noncanonical Wnt pathway. The invasion of Cx43-shRNA S1 cells was observed only under permissive stiffness of the extracellular matrix (ECM). (4) Conclusion: Our results suggest that Cx43 controls proliferation and invasion in the normal mammary epithelium in part by regulating noncanonical Wnt signaling.
Highlights
Connexins (Cxs), the building blocks of the channel-forming gap junctions (GJs), exhibit spatiotemporal expression patterns throughout development of the mammary gland [1,2,3,4,5,6]
Our results suggest that connexin 43 (Cx43) controls proliferation and invasion pathways in the normal mammary epithelium in part via regulating noncanonical Wnt signaling
Earlier studies demonstrated that functional gap junctional intercellular communication (GJIC) and Cx43 interaction with its associated proteins observed in 3-D but not 2-D cultures of mammary epithelial cells are critical for differentiation [62,63]
Summary
Connexins (Cxs), the building blocks of the channel-forming gap junctions (GJs), exhibit spatiotemporal expression patterns throughout development of the mammary gland [1,2,3,4,5,6]. Localization, and function of Cxs have been reported in human breast cancer tissues and in cell lines [9,10,11,12,13,14,15,16] and have been associated with developmental defects in mouse models [17,18,19], suggesting that Cxs have developmental and tumor suppressive roles. Exogenous expression of Cx43 in human breast cancer cell lines reduces proliferation, Cancers 2019, 11, 339; doi:10.3390/cancers11030339 www.mdpi.com/journal/cancers. Silencing Cx43 in Hs578T human breast cancer cell line enhances proliferation and anchorage-independent growth and upregulates the expression of vascular endothelial growth factor (VEGF) [28]. Heterozygous Cx43 mutation enhances the susceptibility to lung metastasis in mice with 7,12-Dimethylbenz(a)anthracene (DMBA)-induced mammary tumors [29]
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