The non-steroidal antiestrogen, tamoxifen, is now accepted as a useful therapeutic agent for the treatment of hormone-dependent breast cancer. However, the pharmacology of antiestrogens has not been systemically investigated and their molecular mechanism of action is unknown. To address these problems, we have developed an estrogen-sensitive pituitary cell culture system. The structure-activity relationship of antiestrogenic ligands in the modulation of prolactin synthesis in rats and mice will be studied following either in vivo treatment of animals or addition of compounds to cultured rat and mouse pituitary cells. We will investigate whether the profound species differences in the action of antiestrogens (rats vs mice) are due to altered ligand requirements or to differential drug metabolism. The basis for the opposite effects on prolactin synthesis of estrogens and antiestrogens GH3 clonal rat pituitary tumor cells - compared to normal pituitary cells - will be studied. In selected experiments, the relative abilities of antiestrogens to inhibit prolactin synthesis and induce progesterone receptors will be compared. Since carcinogen-induced rat mammary cancer is known to be prolactin dependent, our studies will provide precise data on an antitumor mechanism of antiestrogens.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA032713-08
Application #
3170578
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1982-08-01
Project End
1991-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
8
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Pink, J J; Fritsch, M; Bilimoria, M M et al. (1997) Cloning and characterization of a 77-kDa oestrogen receptor isolated from a human breast cancer cell line. Br J Cancer 75:17-27
Pink, J J; Wu, S Q; Wolf, D M et al. (1996) A novel 80 kDa human estrogen receptor containing a duplication of exons 6 and 7. Nucleic Acids Res 24:962-9
Pink, J J; Jordan, V C (1996) Models of estrogen receptor regulation by estrogens and antiestrogens in breast cancer cell lines. Cancer Res 56:2321-30
Pink, J J; Bilimoria, M M; Assikis, J et al. (1996) Irreversible loss of the oestrogen receptor in T47D breast cancer cells following prolonged oestrogen deprivation. Br J Cancer 74:1227-36
Catherino, W H; Jordan, V C (1995) Nomegestrol acetate, a clinically useful 19-norprogesterone derivative which lacks estrogenic activity. J Steroid Biochem Mol Biol 55:239-46
Pink, J J; Jiang, S Y; Fritsch, M et al. (1995) An estrogen-independent MCF-7 breast cancer cell line which contains a novel 80-kilodalton estrogen receptor-related protein. Cancer Res 55:2583-90
Jordan, V C (1994) Molecular mechanisms of antiestrogen action in breast cancer. Breast Cancer Res Treat 31:41-52
Jeng, M H; Jiang, S Y; Jordan, V C (1994) Paradoxical regulation of estrogen-dependent growth factor gene expression in estrogen receptor (ER)-negative human breast cancer cells stably expressing ER. Cancer Lett 82:123-8
Morrow, M; Jordan, V C (1993) Molecular mechanisms of resistance to tamoxifen therapy in breast cancer. Arch Surg 128:1187-91
Jeng, M H; ten Dijke, P; Iwata, K K et al. (1993) Regulation of the levels of three transforming growth factor beta mRNAs by estrogen and their effects on the proliferation of human breast cancer cells. Mol Cell Endocrinol 97:115-23

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