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

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.

SUBMITTER: Thiagarajan PS

PROVIDER: S-EPMC5805730 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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

Thiagarajan Praveena S PS Sinyuk Maksim M Turaga Soumya M SM Mulkearns-Hubert Erin E EE Hale James S JS Rao Vinay V Demelash Abeba A Saygin Caner C China Arnab A Alban Tyler J TJ Hitomi Masahiro M Torre-Healy Luke A LA Alvarado Alvaro G AG Jarrar Awad A Wiechert Andrew A Adorno-Cruz Valery V Fox Paul L PL Calhoun Benjamin C BC Guan Jun-Lin JL Liu Huiping H Reizes Ofer O Lathia Justin D JD

Nature communications 20180208 1

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) ...[more]

PMID: 29422613

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Project description:BackgroundFocal adhesion kinase (FAK) is a cytoplasmatic protein tyrosine kinase that associates with both integrins and growth factor receptors toward the adhesion, migration and invasion of cancer cells. The G-protein coupled estrogen receptor (GPER) has been involved in the stimulatory action of estrogens in breast tumor. In this study, we have investigated the engagement of FAK by GPER signaling in triple negative breast cancer (TNBC) cells.MethodsPublicly available large-scale database and patient data sets derived from "The Cancer Genome Atlas" (TCGA; www.cbioportal.org ) were used to assess FAK expression in TNBC, non-TNBC tumors and normal breast tissues. MDA-MB 231 and SUM159 TNBC cells were used as model system. The levels of phosphorylated FAK, other transduction mediators and target genes were detected by western blotting analysis. Focal adhesion assay was carried out in order to determine the focal adhesion points and the formation of focal adhesions (FAs). Luciferase assays were performed to evaluate the promoters activity of c-FOS, EGR1 and CTGF upon GPER activation. The mRNA expression of the aforementioned genes was measured by real time-PCR. Boyden chamber and wound healing assays were used in order to evaluate cell migration. The statistical analysis was performed by ANOVA.ResultsWe first determined by bioinformatic analysis that the mRNA expression levels of the gene encoding FAK, namely PTK2, is higher in TNBC respect to non-TNBC and normal breast tissues. Next, we found that estrogenic GPER signaling triggers Y397 FAK phosphorylation as well as the increase of focal adhesion points (FAs) in TNBC cells. Besides, we ascertained that GPER and FAK activation are involved in the STAT3 nuclear accumulation and gene expression changes. As biological counterpart, we show that FAK inhibition prevents the migration of TNBC cells upon GPER activation.ConclusionsThe present data provide novel insights regarding the action of FAK in TNBC. Moreover, on the basis of our findings estrogenic GPER signaling may be considered among the transduction mechanisms engaging FAK toward breast cancer progression.

Project description:BACKGROUND & AIMS:Most targeted therapies against cancer are designed to block growth factor-stimulated oncogenic growth. However, response rates are low, and resistance to therapy is high. One mechanism might relate to the ability of tumor cells to induce growth factor-independent proliferation (GFIP). This project aims to understand how (1) cancer cells preferentially derive a major growth advantage by using critical metabolic products of glucose, such as phosphoenolpyruvate (PEP), to drive proliferation and (2) esophageal squamous cell carcinoma (ESCC) cells, but not esophageal adenocarcinoma cells, can induce GFIP by using glycolysis to activate phosphohistidine (poHis)-mediated signaling through focal adhesion kinase (FAK). METHODS:The hypothesis to be tested is that ESCC GFIP induced by glucose is facilitated by PEP-mediated histidine phosphorylation (poHis) of FAK, leading to the possibility that ESCC progression can be targeted by blocking poHis signaling. Biochemical, molecular biological, and in vivo experiments including bromodeoxyuridine/5-ethynyl-2'-deoxyuridine labeling, radioisotope tracing, CRISPR gene editing, and analysis of signaling gene sets in human cancer tissues and xenograft models were performed to define the mechanisms underlying ESCC GFIP. RESULTS:Glucose promotes growth factor-independent DNA replication and accumulation of PEP in ESCC cells. PEP is the direct phospho-donor to poHis58-FAK within a known "HG" motif for histidine phosphorylation. Glucose-induced poHis58 promotes growth factor-independent FAK-mediated proliferation. Furthermore, glucose activates phosphatidylinositol-3'-kinase/AKT via poHis58-FAK signaling. Non-phosphorylatable His58A-FAK reduces xenograft growth. CONCLUSIONS:Glucose induces ESCC, but not esophageal adenocarcinoma GFIP via PEP-His58-FAK-AKT signaling. ESCC progression is controlled by actionable growth factor-independent, glucose-induced pathways that regulate proliferation through novel histidine phosphorylation of FAK.

Dataset Information

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

Publications

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

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