Cx43 deficiency confers EMT-mediated tamoxifen resistance to breast cancer via c-Src/PI3K/Akt pathway

Abstract

Tamoxifen (TAM) resistance has indicated a significant challenge during endocrine therapy for hormone-sensitive breast cancer. Thus, it is significant to elucidate the molecular events endowing TAM resistance to endocrine therapy. In this study, we found that epithelial-mesenchymal transition (EMT) was an important event to confer TAM resistance, and attenuating EMT by elevating connexin (Cx) 43 expression could reverse TAM resistance. Specifically, Cx43 overexpression improved TAM sensitivity, while Cx43 depletion facilitated TAM insensitivity by modulating EMT in T47D TAM-resistant and -sensitive cells, and transplanted xenografts. Importantly, we found a novel reciprocal regulation between Cx43 and c-Src/PI3K/Akt pathway contributing to EMT and TAM resistance in breast cancer. Moreover, we identified that Cx43 deficiency was significantly correlated with poor relapse-free survival in patients undergoing TAM treatment. Therefore, Cx43 represents a prognostic marker and an attractive target for breast cancer treatments. Therapeutic strategies designed to increase or maintain Cx43 function may be beneficial to overcome TAM resistance.

The pro- and anti-tumoral properties of gap junctions in cancer and their role in therapeutic strategies

“…Cell death was induced by activation of the caspase-3 apoptotic pathway [ 119 ]. More recently, similar results were found in breast cancer, in which Cx43 overexpression could attenuate EMT and improve the sensitivity of cancer cells to the chemotherapeutic drug tamoxifen [ 120 ]. EMT is an important event to confer tamoxifen resistance, and overexpression of Cx43 proteins was sufficient to inhibit TGF-β1-induced EMT activation, and to retard PI3K/Akt activation, a signaling pathway that plays a vital role in initiating EMT and drug resistance in different malignancies [ 120 ].…”

“…More recently, similar results were found in breast cancer, in which Cx43 overexpression could attenuate EMT and improve the sensitivity of cancer cells to the chemotherapeutic drug tamoxifen [ 120 ]. EMT is an important event to confer tamoxifen resistance, and overexpression of Cx43 proteins was sufficient to inhibit TGF-β1-induced EMT activation, and to retard PI3K/Akt activation, a signaling pathway that plays a vital role in initiating EMT and drug resistance in different malignancies [ 120 ]. Altogether, these results show that enhancing the tumor-suppressive functions of Cx43 proteins and GJs has the potential to be combined with chemotherapeutic agents in order to overcome chemoresistance.…”

“…Herein, stimulation of Cxs and GJs expression, via gene therapy, has been explored to potentialize anti-cancer drug activity in cancer cells. For instance, Cx43 gene therapy, in which the Cx43 gene is transfected into target cells to promote expression, has been demonstrated to increase cell sensitivity to several chemotherapeutics agents, in different cancer types [ 16 , 119 , 120 ]. In prostate cancer, the combination of Cx43-expressing plasmid DNA and the chemotherapeutic agent docetaxel had significantly stronger anti-cancer effects compared to docetaxel alone, both in vitro and in vivo [ 16 ].…”

Down-regulation of CX43 expression by miR-1 inhibits the proliferation and invasion of glioma cells

“…We applied immunohistochemistry to detect the CX43 protein and in situ molecular hybridization to detect the mRNA expression of CX43 in glioma. At the same time, PCNA was used as an indicator of cell proliferation to analyze the relationship between CX43 gene expression and glioma proliferation and to explore the mechanism of CX43 gene expression and glioma (25)(26)(27).…”

Connexins and Glucose Metabolism in Cancer

“…For example, PI3K/AKT leads to direct phosphorylation of multiple glycolysis enzymes to promote glucose utilization, but can also activate alternative pathways in the absence of glucose [ 249 , 250 , 251 ]. Connexins have been implicated within these signal transduction pathways, including many aspects related to cancer cell function such as motility, invasion, proliferation and therapy resistance [ 252 , 253 , 254 , 255 , 256 , 257 , 258 , 259 , 260 ]. Ongoing studies drawing connections between these growth promoting pathways and their effects on connexins, will undoubtedly continue to converge on metabolic involvement.…”