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

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Annual rept. 1 Oct 97-30 Sep 98

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This research is 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 sensitivityresistance 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 are using these breast cancer cells to study the role of intracellular cAMP in augmentation of antiestrogen agonist activity and in compromising the effectiveness of antiestrogens as estrogen antagonists, which may form the basis for tamoxifen resistance. Understanding the basis for the development of tamoxifen resistance will be important in developing more effective strategies for the successful long-term treatment of hormone-responsive breast cancer.

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  • Biochemistry
  • Medicine and Medical Research

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