TY - JOUR
T1 - Cx26 drives self-renewal in triple-negative breast cancer via interaction with NANOG and focal adhesion kinase
AU - Thiagarajan, Praveena S.
AU - Sinyuk, Maksim
AU - Turaga, Soumya M.
AU - Mulkearns-Hubert, Erin E.
AU - Hale, James S.
AU - Rao, Vinay
AU - Demelash, Abeba
AU - Saygin, Caner
AU - China, Arnab
AU - Alban, Tyler J.
AU - Hitomi, Masahiro
AU - Torre-Healy, Luke A.
AU - Alvarado, Alvaro G.
AU - Jarrar, Awad
AU - Wiechert, Andrew
AU - Adorno-Cruz, Valery
AU - Fox, Paul L.
AU - Calhoun, Benjamin C.
AU - Guan, Jun Lin
AU - Liu, Huiping
AU - Reizes, Ofer
AU - Lathia, Justin D.
N1 - Funding Information:
We thank the members of the Reizes and Lathia laboratories for insightful discussion and constructive comments on the manuscript. We thank Dr. Dale W. Laird (Western University, Ontario, Canada) for providing the Cx26 mutant constructs. We thank Cathy Shemo, Patrick Barrett, Joseph Gerow, and Sage O’Bryant for flow cytometry assistance. We thank Amanda Mendelson for all the illustrations included in this manuscript. This work was funded by National Institutes of Health grant CA191263 to O.R. and J.D.L. This work utilized the Leica SP8 confocal microscope that was purchased from NIH SIG grant 1S10OD019972-01. The Liu laboratory has been supported by NIH/NCI R00CA1606638, American Cancer Society ACS127951-RSG-15-025-01-CSM, Komen CCR15332826, Ohio Cancer Research Associates, and DOD Breast Cancer Research Program BC150596. The work in the Reizes laboratory is also supported by the Cleveland Clinic Foundation, Clinical and Translational Science Collaborative of Cleveland (UL1TR000439), Case Comprehensive Cancer Center (P30 CA043703), and the Cleveland Clinic VeloSano Bike Race (O.R.). The Lathia laboratory also receives funding from the National Institutes of Health (grants NS089641, NS083629, and CA157948); a Distinguished Scientist Award from the Sontag Foundation, a Research Scholar Award from the American Cancer Society, Blast GBM, the Cleveland Clinic VeloSano Bike Race, and the Case Comprehensive Cancer Center.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85041952916&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-02938-1
DO - 10.1038/s41467-018-02938-1
M3 - Article
C2 - 29422613
AN - SCOPUS:85041952916
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 578
ER -
