VE-822 connexins and their cell membrane channels play essential roles in the control of cell proliferation, differentiation and apoptosis and their deregulation can contribute to carcinogenesis including breast cancers. However, no comprehensive study correlating connexin mRNA and protein levels with breast cancer progression and prognosis have been published. Six of the tetraspan transmembrane connexins form hemichannels which can align for gap junctions in adjacent cells allowing the orderly transport of,1,8 kDa regulatory molecules between coupled cells including ions, metabolites, second messengers and morphogenes. Connexins may also function as hemichannels or through intracellular protein-protein interactions with oncogene products such as Src, signaling protein kinases and cytoskeletal elements. More than one of the 21 cloned connexin isotypes are expressed in most human cell types and their importance is reflected by their ubiquitous presence and large density in all solid tissues, early emergence during embryogenesis and high evolutionary conservation throughout vertebrates. Principal connexin functions are related to the maintenance of cell homeostasis and integration of compartmental activities within cell networks. Connexins and gap junctions have long been implicated in tumor suppression. Though connexins can be upregulated in dysplasia or early cancer, their expression and functions are usually reduced in malignant tumors and can be aborted in advanced cancers. However, recent observations suggest a context dependent regulation of connexins in cancer with occasional stage dependent up-regulation. Furthermore, connexin isotypes not found in the normal tissue may also emerge in the related cancer. Available data on connexin expression in normal breast and breast cancer are controversial. Limitations of large scale screening of connexins are explained by scarce antibodies detecting their isotypes in archived tissues and difficulties of resolving the small connexin plaques in,5 mm thick sections. So far, Cx43 and Cx26 have been detected to contribute to human and Cx30 and Cx32 to mouse mammary gland development and lactation. In primary breast cancers Cx43 and Cx26 have been suggested as tumor suppressors. However, increased Cx43, Cx26 and Cx32 protein levels have also been found in lymph node metastases compared to primary breast cancers but without correlation to disease prognosis. Recently, Cx46 has also been implicated in the adaptation of breast cancer cells to hypoxia. Furthermore, heterocellular communication between breast carcinoma cells and vascular endothelia has been confirmed during metastatic tumor invasion. Here, we tested publically available mRNA expression array databases and tissue microarray series of breast cancers for connexin isotype expression. Based on mRNA expression data, a comprehensive screening for five connexin isotypes, GJA1/Cx43, GJA3/Cx46, GJB2/Cx26, GJA6/Cx30 and GJB1/Cx32 was performed at the protein level in normal pre-menopausal breast glands and in a cohort of cancers representing all grades and major breast cancer subtypes. Differential connexin expression showed significant correlations with tumor progression and disease outcome for potential utilization in breast cancer diagnostics and treatment design.