Cyclic AMP Modulation of Estrogen-Induced Effects: A Novel Mechanism for Hormonal Resistance in Breast Cancer

Abstract

Abstract : This research has been aimed at elucidating why breast cancer cells become resistant to antiestrogen treatment. Antiestrogens are used widely in the treatment of breast cancer, and although almost 50% of breast cancer patients benefit substantially from treatment with tamoxifen, many of these women eventually suffer relapse because some of the breast cancer cells become resistant to tamoxifen. We find that cyclic AMP stimulates the agonist activity of tamoxifen-like antiestrogens and reduces the ability of these antiestrogens to suppress estrogen-stimulated activity. In addition, estrogens and antiestrogens increase intracellular cAMP levels, which make tamoxifen more estrogenic and compromise its suppressive ability. We have developed several model breast cancer cell systems that differ in their sensitivity/resistance to antiestrogens and have characterized alterations in their proliferation, their production of and responsiveness to the transforming growth factors alpha and beta, their intracellular cAMP levels, and their production of other estrogen-responsive proteins. We have used these breast cancer cells to study the involvement of intracellular cAMP in augmentation of antiestrogen agonist activity and in compromising the effectiveness of antiestrogens as estrogen antagonists, which can form a basis for tamoxifen resistance. These investigations highlight the important role of cAMP in modulation of estrogen and antiestrogen action in hormonal resistance, and suggest new directions for more effective strategies for the successful long-term treatment of hormone-responsive breast cancer.