The long term objective of this renewal application is to examine the mechanism of the regulation of GJIC and its potential role in carcinogenesis. The working hypothesis which continues to be tested is that down-regulation of GJIC, at the transcriptional, translational or posttranslational levels by oncogenes, chemical tumor promoting agents, and specific hormones and growth factors, permits initiated cells to escape the suppressing effects of surrounding and communicating cells. Based on (a) the demonstration that many chemical tumor promoters (i. e., TPA, DDT, TCDD, saccharin, phenobarbital, etc.), growth factors (EGF, TGF- a), oncogenes (src, ras, raf, neu, mos) down-regulate GJIC; (b) approximately 14 gap junction genes have been isolated; (c) many new techniques to measure the function of GJ's have been developed; (d) anti-tumor promoting chemicals (retinoids, carotenoids, green tea components, etc.) have been shown to up-regulate GJIC; and (e) genetic engineering of non-communicating cancer cells or of normal communicating cells with specific GJ genes or anti- sense GJ gene, respectively, alters growth regulation in these cells, this application is designed to examine three specific aims to build on the applicant's previous contribution to this field.
The first aim i s to study the specific signal transducing mechanisms which might be associated with either chemical, growth factor or oncogene modulation of GJIC and the biological effects on cell proliferation or differentiation.
The second aim i s to study the potential role of various tumor suppressor genes in the up-regulation of GJIC.
The third aim will utilize a unique in vitro cell differentiation model system, normal human breast epithelial putative stem cells, to study the potential role of GJ's in differentiation in order to link the blockage of GJIC and differentiation in carcinogenesis. Logic tree of this application is that GJIC in a multicellular organism is obligatory for the regulation of cell proliferation and differentiation in solid tissues. Reversible modulation of GJIC is done by extracellular communication signals which could trigger signal transduction within a cell to modulate GJ's at the transcriptional, translational or post- translational levels in normal cells. Cancer, a disease of cell proliferation and differentiation, would appear to have been blocked somewhere in the link between extra-, intra- and GJIC-intercellular communication. The proposed studies are designed to test this hypothesis.
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