Modulation of gap junctional intercellular communication during human breast stem cell differentiation and immortalization

The gap junctional exchange of ions or small molecules, including second messenger such as cAMP and Ca2+ between adjacent cells, plays an essential role in the maintenance of homeostasis, coordination of secretion, morphogenesis, cell differentiation, and growth control in multicellular organs. Aberrant gap junctional intercellular communication (GJIC) has been implicated in tumor promotion, neuropathy and teratogenesis. We have isolated and characterized two types of normal human breast epithelial cells with stem cell characteristics (Type I) or basal epithelial cell characteristics (Type II). Furthermore, we have demonstrated that Type I normal human breast epithelial cells (HBEC) with stem cell characteristics were gap junctional intercellular communication (GJIC)-deficient while Type II HBEC with basal epithelial characteristics were GJIC-efficient. Using cholera toxin, we have also shown that human breast stem cells could differentiate into basal epithelial cells. This study showed that Type I HBEC could differentiate into Type II HBEC using cholera toxin or forskolin treatment. These differentiated cells have GJIC activity. In addition, these differentiated cells from Type I HBEC expressed connexin 43 (Cx43). We have developed SV40 immortalized cell lines from a normal human breast epithelial cell(HBEC) type with basal epithelial cell characteristics, and we examined the modulation of GJIC during immortalization. GJIC activity was reduced in the extended-life span and immortalization state of Type II HBEC. The phosphorylation pattern of Cx43 was altered during immortalization. Taken together, these results indicated that the modulation of GJIC might be crucial in human breast differentiation and carcinogenesis.