Utilizing MCF-7 human breast cancer cells as a model system, it is the objective of these investigations to relate certain changes in the functional and structural features of estradiol-17Beta (E2) to responses elicited by the receptor-ligand complex. Numerous reports have associated the various elements of such antiestrogen structures as tamoxifen with specific responses in target cells. Likewise, our preliminary experiments have suggested that particular structural components of E2 are responsible for certain responses in cancer cells. It is postulated that the change in tertiary structure of the estrogen receptor complex, brought about by specific alterations in the molecule of the estrogen ligand, results in quantitative and/or qualitative alterations in cellular responses. Specifically, it is the purpose of this project to synthesize a wide range of positional isomers of E2, as well as introduce additional functional groups into the natural estrogens. Precise changes in the structure of estrogen will be related to the stimulatory properties of the resulting receptor-estrogen complex. These experiments will examine the altered estrogens for their ability to bind to receptor and bring about """"""""high affinity"""""""" nuclear uptake and """"""""processing"""""""" of the complex. In addition, the estrogen analogue-receptor complex will be examined for its binding to specific regions of the chromatin acceptor site and to DNA. The capacity of each altered estrogen to elicit pS2 mRNA transcription and the induction of progesterone receptor, plasminogen activator and the 52KDa protein will be determined. Finally, the effect of each of the structural components of E2 on the growth of MCF-7 cells, as well as on their uterotrophic potency will be ascertained. The information is expected to provide insights to facilitate the development of agents which possess only the desired function of E2 for the treatment of hormone-dependent neoplasms or for use in fertility control without the undesirable side effects.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA044771-01
Application #
3187556
Study Section
Reproductive Endocrinology Study Section (REN)
Project Start
1987-04-15
Project End
1990-03-31
Budget Start
1987-04-15
Budget End
1988-03-31
Support Year
1
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Wayne State University
Department
Type
Schools of Medicine
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202
Brooks, Sam C; Skafar, Debra F (2004) From ligand structure to biological activity: modified estratrienes and their estrogenic and antiestrogenic effects in MCF-7 cells. Steroids 69:401-18
Davis, M D; VanderKuur, J A; Brooks, S C (1999) Ligand structure influences autologous downregulation of estrogen receptor-alpha messenger RNA. J Steroid Biochem Mol Biol 70:27-37
Schwartz, J A; Liu, G; Brooks, S C (1998) Genistein-mediated attenuation of tamoxifen-induced antagonism from estrogen receptor-regulated genes. Biochem Biophys Res Commun 253:38-43
Schwartz, J A; Brooks, S C (1997) Neutral mutations to three acidic AF2 residues in the mouse estrogen receptor confer agonist activity to A-ring isomers of estradiol. J Steroid Biochem Mol Biol 62:173-84
Wiese, T E; Polin, L A; Palomino, E et al. (1997) Induction of the estrogen specific mitogenic response of MCF-7 cells by selected analogues of estradiol-17 beta: a 3D QSAR study. J Med Chem 40:3659-69
Palomino, E; Heeg, M J; Pilat, M J et al. (1996) Crystal structure, receptor binding, and gene regulation of 2- and 4-nitroestradiols. Steroids 61:670-6
Pilat, M J; Christman, J K; Brooks, S C (1996) Characterization of the estrogen receptor transfected MCF10A breast cell line 139B6. Breast Cancer Res Treat 37:253-66
Wiese, T E; Dukes, D; Brooks, S C (1995) A molecular modeling analysis of diethylstilbestrol conformations and their similarity to estradiol-17 beta. Steroids 60:802-8
Davis, M D; Butler, W B; Brooks, S C (1995) Induction of tissue plasminogen activator mRNA and activity by structurally altered estrogens. J Steroid Biochem Mol Biol 52:421-30
Christman, J K; Nehls, S; Polin, L et al. (1995) Relationship between estrogen structure and conformational changes in estrogen receptor/DNA complexes. J Steroid Biochem Mol Biol 54:201-10

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