Abstract
PurposeGap junctions are specialized membrane structures that form channels between adjacent cells allowing cell communication. Gap junctions and specifically Connexin 43 (Cx43) are down-regulated in cancer; however, there are contrasting reports on how this effects breast cancer patient survival. This paper is the first large-scale tissue microarray analysis of Cx43 expression in breast cancer patients with an associated clinical long-term follow-up.MethodsUsing a validated TMA of 1118 primary breast cancers, coupled to a comprehensive database of clinicopathological variables, the expression levels and subcellular localisation of Cx43 was assessed by immunohistochemistry. Its impact in terms of survival, distant metastasis-free survival, and clinicopathological variables was determined.ResultsPatients whose tumors expressed high levels of Cx43 had significantly better survival (p < 0.001) than patients with low levels. High Cx43 expression within tumors was associated with an 18-month survival advantage. Loss of Cx43 expression was associated with markers of poor prognosis, namely large tumor size, high grade, high proliferation status, high pleomorphism, high mitosis, poor Nottingham Prognostic Index (NPI), and triple negative tumors. Cx43 expression was independent of tumor size, grade, stage and ER-status in predicting poor survival on multivariate analysis (p = 0.004).ConclusionConnexin 43 (Cx43) is an independent predictor of breast cancer survival and distant metastasis-free survival. High expression of Cx43 was seen in only 13% of tumors, suggesting that drugs to increase Cx43 expression may result in prolonged patients survival.
Highlights
Connexin 43 (Cx43) has dual functions due to its involvement in cell-to-cell communication through gap junctions and in maintenance of homeostasis
We demonstrate that Cx43 expression in either the membrane or cytoplasm is an independent predictor of survival, it is an independent predictor of distant metastasis-free survival in breast cancer
A tissue microarray (TMA) series of 1980 breast patients was immunoprobed for Cx43 expression
Summary
Connexin 43 (Cx43) has dual functions due to its involvement in cell-to-cell communication through gap junctions and in maintenance of homeostasis. Gap junctions are specialized membrane structures that permit the formation of channels between adjacent cells. Two hemi-channels (made up of 6 connexins) pair to form an intracellular gap junction channel allowing the passage of second messengers, ions and other small molecules (< 1000 Da), in a process known as gap junctional intracellular communication (GJIC) [1]. The carboxyl-terminus (C-terminus) regulatory domain of Cx43 is located in the cytoplasm. This is the primary site of its protein:protein interactions and phosphorylation and has been demonstrated to have a role in its intracellular functions such as proliferation, apoptosis, and migration [2].
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