Deregulation of connexins and their cell membrane channels has been implicated in breast carcinogenesis and tumor progression, however, prognostic correlations of connexins have been rarely found. In this study, recent advances in probe specificity and detection sensitivity allowed the correlation of connexin mRNA and protein levels with breast AbMole BioScience Life Science Reagents cancer prognosis at unique quality. We disclosed the expression of five connexin isotypes by confirming the production of GJA1/Cx43, GJA3/Cx46 and GJB2/Cx26 and detecting, for the first time, GJA6/Cx30 and GJB1/Cx32 both in the human pre-menopausal mammary gland and breast carcinomas. Transcriptomic analysis of both array datasets, Affymetrix and Illumina of,2000 patients each, cross-validated each other’s results. In line with the correlations found at mRNA level, elevated Cx43 protein levels were linked with significantly improved breast cancer outcome, offering Cx43 protein detection as an independent prognostic marker outperforming vascular invasion or necrosis. As a contrary, elevated Cx30 mRNA and protein levels were associated with a reduced disease outcome offering Cx30 protein detection as an independent prognostic marker outperforming MI or necrosis. The prognostic value of the rest of connexin isotypes revealed at mRNA level was either lost or was discordant with that observed at protein level suggesting a complex regulation of these isotypes involving significant post-transciptional/2translational control for further clarification. These data show that differential connexin expression may serve as a potential marker of breast cancer prognosis. Most data on the regulation of connexin expression are related to Cx43, which had good prognostic correlations between mRNA and protein levels in this study. The tested gene array data suggest that in ER positive primary breast cancers Cx43 mRNA expression can be linked with tumor suppression, while in ER negative cases with tumor protection. 17b estradiol through ERa can promote both the proliferation of mammary epithelial cells and the expression and functions of Cx43 channels, which are implicated in cell cycle control. The potential control of tumor growth by Cx43 is likely to contribute to the better differentiation and improved patient survival of ER positive tumors. In ER negative breast cancers other pathways dominate in Cx43 expression potentially involving Wnt-1 and/or Ras-Raf-MAPK activation, which can also be part of mitogenic signaling responsible for the less differentiated phenotype and worse prognosis. In these advanced tumors, connexins can also contribute to metastatic invasion, transendothelial diapedesis and colonization of breast cancer cells in line with the observations made by several studies. ER subtypes may also influence disease outcome since activating ERb may suppress both Cx43 expression and tumor growth ; so as posttranslational regulation since Cx43 protein levels were not linked to a prognostic inversion seen at mRNA level in ER negative cases. The prognostic value of Cx43 was preserved after hormone therapy, implying that Tamoxifen or aromatase inhibitors can block mitogenic signaling without significantly reducing Cx43 expression and functions.