We have demonstrated that cyclic adenosine 3',5'-monophosphate (cAMP) and its binding proteins are involved in the regulation of the growth of mammary tumors in experimental animals. Whilst human breast cancers which possess estrogen receptor (ER) and progesterone receptor (PgR) activities are likely to be hormone responsive, many do not respond to endocrine therapy. In hormone-dependent rat mammary tumors the ratio of steroid receptors to cAMP binding proteins was found to better discriminate hormone-dependent from independent tumors than steroid receptor alone. In this study we investigated the relationship between cAMP binding proteins, ER and PgR in human breast cancers and clinical parameters including prognosis. Several molecular species as well as proteolytic fragments of cAMP binding proteins have been found in normal and neoplastic tissues. The molecular species of cAMP binding proteins were determined by the photo-incorporation of 8-azido-(P32) cAMP and the immunoprecipitation using affinity purified antibodies to cAMP binding proteins. Utilizing immunocytochemical method intracellular distribution and nuclear compartmentalization of cAMP binding proteins were also determined. Finally, in a cell-free system, the binding of cAMP binding proteins directly to DNA of normal vs cancer cells was studied. The goal of this proposal is to elucidate the fundamental growth regulatory mechanism of cAMP which can be applied to the breast cancer therapy.
