The objective of this proposal is to determine how changes in expression of properties of normal cell differentiation and maturation are related to the carcinogenic process in human epithelial cells. For our purposes, the stages of maturation and differentiation will be evaluated by glucose metabolite pattern, synthesis of milk components, presence and cellular concentration of mammary specific enzymes, synthesis of cytoskeletal elements, and the synthesis and arrangement of cell surface and extracellular matrix proteins. The culture variables to be tested include medium composition, cell shape and polarity, and the composition of extracellular matrices. Comparisons among normal cells, cells autogenic to normal but transformed in vitro by chemical carcinogen treatment, and cells grown out from mammary tumors will be used to assess the influence of carcinogenesis on functional differentiation. The human mammary epithelial culture system was chosen for this purpose because: (1) cells can be grown out from normal and cancerous tissues in a serum-free medium for 40 to 60 population doublings; (2) large cell pools are available for experimentation; (3) mammary epithelial cells possess unique properties for evaluating the functional differentiated state; (4) phenotypic expression by these cells can be modulated in culture; (5) a progressive series of cell strains with extended life, continuous cell lines, and malignant transformants that are autogenic to normal human mammary epithelial cells are available for study; (6) malignant transformation in epithelial cells has been related to aberrant expression of normal differentiated states; and (7) in breast cancer, epidemiological and experimntal evidence point to a relationship between the risk of cancer and the developmental or differentiated state. These studies could provide insights into the sites for control of normal differentiated function, the factor(s) involved, and possible sites of aberrant expression in transformation and, thus, provide a sound basis for investigations in the future into the molecular mechanisms controlling gene expression in regulating normal functional differentiation and the aberrations which occur during transformation. (S)
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