Next Article in Journal
The Stem Cell Phenotype of Aggressive Breast Cancer Cells
Next Article in Special Issue
Pannexin 2 Localizes at ER-Mitochondria Contact Sites
Previous Article in Journal
Chemotherapy Resistance Explained through Endoplasmic Reticulum Stress-Dependent Signaling
Previous Article in Special Issue
Insight into the Role and Regulation of Gap Junction Genes in Lung Cancer and Identification of Nuclear Cx43 as a Putative Biomarker of Poor Prognosis
Article Menu
Issue 3 (March) cover image

Export Article

Open AccessArticle
Cancers 2019, 11(3), 339; https://doi.org/10.3390/cancers11030339

Connexin 43 Loss Triggers Cell Cycle Entry and Invasion in Non-Neoplastic Breast Epithelium: A Role for Noncanonical Wnt Signaling

1
Department of Biology, Faculty of Arts and Sciences, American University of Beirut (AUB), Beirut 11-0236, Lebanon
2
Department of Natural Sciences, School of Arts and Sciences, Lebanese American University (LAU), Beirut 11-0236, Lebanon
3
Department of Basic Medical Sciences, Purdue University, 47907, West Lafayette, IN, USA
4
Purdue University Center for Cancer Research, 47907, West Lafayette, IN, USA
*
Author to whom correspondence should be addressed.
Received: 3 January 2019 / Revised: 15 February 2019 / Accepted: 4 March 2019 / Published: 8 March 2019
Full-Text   |   PDF [3579 KB, uploaded 26 March 2019]   |  
  |   Review Reports

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. View Full-Text
Keywords: mammary gland; mammary epithelium; breast cancer; gap junctions; connexin 43; Wnt pathways; proliferation; motility; invasion; microenvironment mammary gland; mammary epithelium; breast cancer; gap junctions; connexin 43; Wnt pathways; proliferation; motility; invasion; microenvironment
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

Supplementary material

SciFeed

Share & Cite This Article

MDPI and ACS Style

Fostok, S.; El-Sibai, M.; Bazzoun, D.; Lelièvre, S.; Talhouk, R. Connexin 43 Loss Triggers Cell Cycle Entry and Invasion in Non-Neoplastic Breast Epithelium: A Role for Noncanonical Wnt Signaling. Cancers 2019, 11, 339.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Cancers EISSN 2072-6694 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top