| This dissertation presents the results of an integrated study of the biochemical parameters which appear to mediate the growth and regression of hormone dependent rat mammary tumors. These tumors regress upon ovariectomy, due to withdrawal of estrogen, and possibly more importantly, a concommitant decrease in prolactin. An elevation of prostaglandin synthesis, especially of PGE(,2), was demonstrated in 7,12-dimethylbenz(a)a nthracene (DMBA)-induced mammary tumors which were regressing as compared to growing tumors. The modification of a new method for the measurement of prostaglandin release from tumor tissue slices was presented. PGE(,2) binding to the DMBA-induced mammary tumors was observed, and exogenous PGE(,2) stimulated an elevation in cAMP content in these tumors. Cyclic AMP content in growing and regressing tumors paralleled PGE(,2) production, a higher cAMP concentration being present in regressing tumors than in growing tumors. Prostaglandin binding and the ability to synthesize cAMP were two characteristics of hormone dependent rat mammary tumors which were shown to be deficient in hormonally independent rat mammary tumors. Furthermore, PGE(,2) binding activity and cAMP content were greater in regressing tumors than in growing tumors in another model of hormone dependent rat mammary cancer, the transplantable MTW9-A tumors. Markedly enhanced specific phosphorylation of a 76,000 dalton regression associated protein, associated with the elevation of cAMP and related biochemical changes, was demonstrated in the nuclei of regressing DMBA-induced tumors.; It is hypothesized that these biochemical changes act in a sequential manner to mediate the regression of hormonally-dependent rat mammary cancer, induced by specific hormone withdrawal. Conversely, the data suggest that low levels of cAMP and PGE(,2) maintained by the presence of physiological levels of prolactin (and estrogen), represent an environment supportive of the growth of hormone dependent rat mammary tumors. |
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