Cx26 drives self-renewal in triple-negative breast cancer via interaction with NANOG and focal adhesion kinase

Praveena S. Thiagarajan, Maksim Sinyuk, Soumya M. Turaga, Erin E. Mulkearns-Hubert, James S. Hale, Vinay Rao, Abeba Demelash, Caner Saygin, Arnab China, Tyler J. Alban, Masahiro Hitomi, Luke A. Torre-Healy, Alvaro G. Alvarado, Awad Jarrar, Andrew Wiechert, Valery Adorno-Cruz, Paul L. Fox, Benjamin C. Calhoun, Jun-Lin Guan, Huiping Liu, Ofer Reizes () and Justin D. Lathia ()
Additional contact information
Praveena S. Thiagarajan: Cleveland Clinic
Maksim Sinyuk: Cleveland Clinic
Soumya M. Turaga: Cleveland Clinic
Erin E. Mulkearns-Hubert: Cleveland Clinic
James S. Hale: Cleveland Clinic
Vinay Rao: Cleveland Clinic
Abeba Demelash: Cleveland Clinic
Caner Saygin: Cleveland Clinic
Arnab China: Cleveland Clinic
Tyler J. Alban: Cleveland Clinic
Masahiro Hitomi: Cleveland Clinic
Luke A. Torre-Healy: Cleveland Clinic
Alvaro G. Alvarado: Cleveland Clinic
Awad Jarrar: Cleveland Clinic
Andrew Wiechert: Cleveland Clinic
Valery Adorno-Cruz: Case Comprehensive Cancer Center
Paul L. Fox: Cleveland Clinic
Benjamin C. Calhoun: Cleveland Clinic
Jun-Lin Guan: University of Cincinnati
Huiping Liu: Case Comprehensive Cancer Center
Ofer Reizes: Cleveland Clinic
Justin D. Lathia: Cleveland Clinic

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract Tumors adapt their phenotypes during growth and in response to therapies through dynamic changes in cellular processes. Connexin proteins enable such dynamic changes during development, and their dysregulation leads to disease states. The gap junction communication channels formed by connexins have been reported to exhibit tumor-suppressive functions, including in triple-negative breast cancer (TNBC). However, we find that connexin 26 (Cx26) is elevated in self-renewing cancer stem cells (CSCs) and is necessary and sufficient for their maintenance. Cx26 promotes CSC self-renewal by forming a signaling complex with the pluripotency transcription factor NANOG and focal adhesion kinase (FAK), resulting in NANOG stabilization and FAK activation. This FAK/NANOG-containing complex is not formed in mammary epithelial or luminal breast cancer cells. These findings challenge the paradigm that connexins are tumor suppressors in TNBC and reveal a unique function for Cx26 in regulating the core self-renewal signaling that controls CSC maintenance.

Date: 2018
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DOI: 10.1038/s41467-018-02938-1

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