Gap junction genes Cx26 and Cx43 individually suppress the cancer phenotype of human mammary carcinoma cells and restore differentiation potential.
Normal human mammary epithelial cells express hcx43 and hCx26 proteins, which form functional gap junction channels. Both Cx genes are transcriptionally down-regulated in mammary carcinoma cell lines; consequently, no protein is made and gap junctions are absent. This result suggests that the loss of gap junctional communication may play an important role in carcinogenesis. To address this question, two sets of stable transfectants were produced in a recloned line of human mammary carcinoma cells (MDA-MB-435). One set expressed hCx26, and the other expressed hCx43. Studies of transfectants that contain functional gap junctions showed that they grew more slowly in culture than controls, and that their tumor-forming ability was strongly suppressed. In studies designed to examine their differentiation capacity, these transfectants were found to have regained the capacity to form three-dimensional structures in a matrigel matrix. This property is characteristic of normal mammary epithelial cells, but it is lost in the parental tumor cells and neo-transfectant controls. Thus, junctional communication is shown here to play a decisive role in the morphogenesis of mammary gland structures. The hCx26 and hCx43 genes behave as classical tumor suppressor genes both in culture and in animal tests in restoring growth regulatory properties to metastatic mammary carcinoma cells. Expression of these genes further induces the ability to differentiate as shown by the formation of three-dimensional structures when transfected cells are embedded in a matrigel matrix. These findings suggest that the reexpression of gap junctions may play a vital role in normalizing tumor cell behavior.
Hirschi
K K
KK
Division of Cancer Genetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Xu
C E
CE
Tsukamoto
T
T
Sager
R
R
D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D000072259:Connexin 26; D018031:Connexin 43 / Q000235:genetics*; D017630:Connexins / Q000235:genetics*; D005260:Female; D017629:Gap Junctions / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D016147:Genes, Tumor Suppressor; D006801:Humans; D014407:Tumor Cells, Cultured
D018031:Connexin 43; D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26