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Abstract
Connexins regulate multiple cellular functions and are considered tumor suppressors. Connexin43 (Cx43) is frequently down-regulated in breast tumors. However, Cx43 regulation during cancer onset and metastasis is complex and context-dependent. We investigated the effect of Cx43 over-expression or knock-down on the metastatic potential of MDA-MB-231 breast cancer cells in vitro and in vivo and in human breast cancer tissues. MDA-MB-231 cells over-expressing (Cx43D) or down-regulating Cx43 (shCx43) were generated and used in proliferation, migration, and invasion assays. The regulation of genes/proteins implicated in progression, invasion and metastasis was assessed in vitro and in immune-compromized mice injected with MDA-MB-231, Cx43D or shCx43 cells. Primary tumor onset/growth, metastasis and overall survival of these animals was monitored and evaluated. In addition, Cx43 expression in human breast carcinoma samples was assessed by qPCR. Cx43 over-expression increased protein levels of epithelial markers E-cadherin and zonula occludens 1 expression and resulted in the sequestration of β-catenin at the cell membrane, while Cx43 knock-down induced protein expression of the mesenchymal marker N-cadherin and an increased invasive potential of shCx43 cells. In vivo, in mice xenografted with breast cancer cells, Cx43 over-expression decreased tumor volume, attenuated cell metastasis to lungs and liver and increased overall mice survival. Importantly, the expression of Cx43 in triple negative human breast cancer tissues is also down-regulated. Collectively, Cx43 over-expression induced an epithelial-like phenotype in MDA-MB-231 cells and suppressed tumor growth and metastasis to secondary organs in vivo. In contrast, Cx43 knock-down in MDA-MB-231 cells induced a mesenchymal phenotype with increased cell invasion leading to an enhanced metastatic phenotype. These data provide evidence for a pivotal role of Cx43 in breast cancer metastasis and support the potential targeting of connexins in breast cancer therapy.
Highlights
Metastasis, the colonization of tumor cells into selective secondary organ sites from a primary location [1,2,3], accounts for more than 90% of cancer-related mortality
Studies have reported that Cx26 and Cx43 were up-regulated in lymph node metastases [19] and that gap junctional communication is essential in breast cancer progression at extravasation sites [18]
Potential for Cx43 to suppress the malignant phenotype of breast cancer cells
Summary
Metastasis, the colonization of tumor cells into selective secondary organ sites from a primary location [1,2,3], accounts for more than 90% of cancer-related mortality. Studies have reported that Cx26 and Cx43 were up-regulated in lymph node metastases [19] and that gap junctional communication is essential in breast cancer progression at extravasation sites [18]. Over-expression of connexins reduced the proliferation and malignant phenotype of breast cancer cells in vitro and in vivo [11,20,21,22,23]. Connexin down-regulation caused an aggressive phenotype in breast cancer cells in vitro, where cell proliferation, migration and angiogenesis-related genes were induced [25]. Notwithstanding, other studies have attributed a cancer-promoting role for connexins [19,29,30,31,32,33,34,35,36]
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