Our studies of the pathogenesis an deprevention of mammary cancer led us to conclude that diffentiation is an effective and physiologic mechanism for preventing chemically induced mammary carcinogenesis, since the fully differentiated mammary gland of parous rats is refractory to the initiation of 7, 12-demethylbenz(a)anthracene (DMBA_-induced mammary carcinomas. The observations that this effect is mimicked by treatment of young virgin rats with the placental hormone chorionic gonadotropin (CG), which also prevent the progression of the tumors, making this model ideal for its utilization in human breast cancer prevention and therapy of the human disease. The finding that hCG induces in the mammary gland profuse lobular formalin and the expression of inhibin led us to postulate that the action of hCG might be mediated by this inhibitor growth factor which might act as a local regulatory factor. We will apply our experience on the pathogenesis of DMBA-induced mammary cancer for identifying intraductal proliferations (IDPs), in situ carcinomas and invasive carcinomas to test the effect of hCG on these lesin. We propose to clarify whether hCG inhibit tumorigenesis by inducing differentiation of the neoplastically initiated cells, whether it merely inhibits cell proliferation, or drives the cells to programmed cell death. In this setting, we will define differentiation by the ability of the neoplastically initiated cells to synthesize the milk protein beta casein and inhibin; cell proliferation will be measured by the ability of the cells to incorporate DNA precursors and the number of cells undergoing programmed cell death will be measured in the same tumors by determining the expression of transforming growth factor (TGF)beta1, by detection of the TRPM-2 gene and by measuring he apoptotic index. With this methodology, we propose to investigate the mechanism(s) by which hCG inhibits the progression of DMBA-induced rat mammary carcinomas by determining whether tumor growth is modulated by induction of cell differentiation, inhibition of cell proliferation and/or activation of programmed cell death. We also propose to determine whether the inhibitory effect of hCG on tumor progression is a direct effect of the hormone on tumor cells effected by the binding of hCG to a specific lutropin-choriogonadotropin receptor (LH-CG-R), whether this receptor is treatment or by hCG itself; and finally, we propose to determine what is the direct effect of inhibin on mammary tumors and whether it is the mediator of the differentiations effect of hCG on the mammary gland. The answer to these questions will help to determine whether hormonally induced differentiation is a plausible mechanism for developing more rationale bases for cancer prevention and therapy.
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