A growing body of evidence indicates that the gap junction (GJ) plays a pivotal role in tumor suppression by exerting cell-cell communication. It has, however, been reported that expression of connexin26 (Cx26) protein is induced in human ductal carcinomas of the breast and that its amount increases in proportion to the grade of malignancy. We thus examined the effects of overexpressed Cx26 on growth characteristics in GJ-deficient human MCF-7 breast cancer cells that maintain the phenotype of earlystage cancers. MCF-7 cells were transfected with Cx26 cDNA, and several clones of stable transformants exhibiting a high level of cell-cell communication were established. When they were examined in terms of various growth characteristics in vitro, the proliferation rate and the saturation density were drastically reduced in Cx26-transfected clones compared with the mock-transfectant. The anchorage-independent growth capacity was also decreased by 50-75% after transfection of Cx26. Furthermore, the cell migration toward growth factors and cell invasion into Matrigel in a Boyden chamber were suppressed to 5-10% and 20-60%, respectively, of the control in Cx26-transfected clones. When implanted into the mammary fat pads of nude mice in the presence of an excess of 17β β β β-estradiol, Cx26-transfected clones tended to show slower tumor growth than the mock-transfectant, although the difference was not statistically significant. Our results strongly suggest that the induction of Cx26 protein observed in human breast cancers, reported previously, may not be very relevant to the development of breast cancers, and that Cx26 can function as a tumor suppressor in breast cancer cells. (Cancer Sci 2003; 94: 501-507) omeostasis in cellular society is an important factor for maintenance of tissue function, and its disorder often results in dysfunction of organs and development of diseases including cancers. Among cellular apparatuses that contribute to tissue homeostasis, the gap junction (GJ) mediates gap junctional intercellular communication (GJIC) and is unique in that tiny water-soluble molecules (M r <1000), such as inorganic ions, small metabolites and some second messengers, can travel directly between two adjacent cytoplasms through the junction.1) A gap junctional channel consists of two membrane-integrated hemichannels provided by each of two adjacent cells, and each hemichannel comprises a hexameric complex of connexin protein. The connexin multigene family is composed of at least 20 members in mammals. 2)Many studies have so far proved that down-regulation of the GJ is involved in carcinogenic pathways and that connexin proteins can function as tumor-suppressors. 3,4) In almost all tumors, the function of the GJ is down-regulated through one or more of a variety of mechanisms, including no or reduced expression, aberrant localization, and aberrant phosphorylation or dephosphorylation of connexin protein. Moreover, enforced expression of connexin protein very often abolishes the growth capacity of transformed cells su...

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