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 trans criptionally downregulated in mammary carcinoma cell lines; consequent ly, no protein is made and gap junctions are absent, This result sugge sts that the loss of gap junctional communication may play an importan t role in carcinogenesis, To address this question, two sets of stable transfectants were produced in a recloned line of human mammary carci noma cells (MDA-MB-435), One set expressed hCx26, and the other expres sed hCx43. Studies of transfectants that contain functional gap juncti ons showed that they grew more slowly in culture than controls, and th at their tumor-forming ability was strongly suppressed, In studies des igned to examine their differentiation capacity, these transfectants w ere found to have regained the capacity to form three-dimensional stru ctures 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 st ructures. The hCx26 and hCx43 genes behave as classical tumor suppress or genes both in culture and in animal tests in restoring growth regul atory properties to metastatic mammary carcinoma cells, Expression of these genes further induces the ability to differentiate as shown by t he formation of three-dimensional structures when transfected cells ar e embedded in a matrigel matrix. These findings suggest that the reexp ression of gap junctions may play a vital role in normalizing tumor ce ll behavior.