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

摘要

This research is aimed at elucidating why breast cancer cells become resistant toantiestrogen 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 rAMP 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 a and beta, their intracellular cAMP levels, and their production of other estrogen-responsive proteins.