Connexin 43 in the development and progression of breast cancer: What's the connection? (Review)

Abstract

Connexin 43 is a prominent gap junction protein within normal human breast tissue. Thus far, there have been a number of research studies performed to determine the function of connexin 43 in breast tumor formation and progression. Within primary tumors, research suggests that the level of connexin 43 expression in breast tumors is altered when compared to normal human breast tissue. While some reports indicate that connexin 43 levels decrease, other evidence suggests that connexin 43 levels are increased and protein localization shifts from the plasma membrane to the cytoplasm. In either case, the prevailing theory is that breast tumor cells have reduced gap junction intercellular communication within primary tumors. The current consensus appears to be that the loss of connexin 43 gap junction intercellular communication is an early event in malignancy, with the possibility of gap junction restoration in the event of metastasis. However, additional evidence is needed to support the latter claim. The purpose of this report is to review the connexin 43 literature that describes studies using human tissue samples, in order to evaluate the function of connexin 43 protein in normal human breast tissue as well as the role of connexin 43 in human breast tumor formation and metastatic progression.

Figure 1

Gap junctions are the structures that allow for communication between individual cells via the direct intercellular exchange of secondary messengers, small metabolites and inorganic ions. Gap junctions are located at the plasma membrane and connect neighboring cells (A). Each gap junction is composed of two hemi-channels known as connexons and each connexon is comprised of six oligomerized protein subunits called connexins (B).

Figure 2

Early stages of breast cancer are thought to be marked by a loss of gap junctions leading to the development of a primary tumor (A). Migration of primary tumor cells into the circulation is part of the inital steps of metastasis. It is thought that gap junction intercellular communication is lost during this initial process and following, a possible reformation of gap junction intercellular communication may occur (B).