Mechanisms of estrogen action

Estrogens regulate a variety of cellular and developmental responses, through interaction of the hormone with specific receptors of the nuclear receptor superfamily. After binding an estrogen, the receptor-estrogen complex mediates changes in transcription in the nucleus of the cell that lead to specific hormonal responses. Dr. Welshons' lab studies the mechanisms by which estrogens regulate the synthesis and degradation of the estrogen receptor protein and message in estrogen-responsive MCF-7 human breast cancer cells, mechanisms of estrogen-stimulated proliferation, and the progression of breast cancer cells from hormone dependence to hormone independence. In addition, his lab studies estrogen action in fetal development, its relationship to environmental xenoestrogen exposure, and the mechanisms and prediction of environmental endocrine disruptor effects on the development of the reproductive tract. One current focus in this is how the physiology of delivery of environmental estrogens can substantially increase the impact of selected environmental estrogens on fetal development, relative to weak activity in the adult. This work on circulating xenobiotic estrogens studied in tissue culture models, tested in animal models in collaboration with F.S. vom Saal also at this institution, contributes to the national regulatory process for the evaluation of endocrine disruption by synthetic chemicals.

Research Funding [ top ]

1. Behavior of estrogen receptor transferred into cells, NSF Predoctoral Fellowship, $12,300, 100%, 9-73 to 8-76.

2. Nuclear translocation of transferred estrogen receptor, F32 HD06008, NIH Postdoctoral Fellowship (Individual NRSA), $37,420, 100%, 11-80 to 10-82.

3. Localization of steroid hormone receptors using cytochalasin-induced enucleation, IN-35X-11, PI, ACS Institutional Research Grant, $2150, 10-83 to 6-84.

4. Turnover of steroid receptors in enucleated MCF-7 cells, MOV-1-26, PI, CVM COR, $2111, 5%, 7-88 to 5-89.

5. Cell enucleation to study steroid receptor turnover, BR 3415, PI, UMC Res. Council, $7500, (equipment), 7-88 to 6-89.

6. Regulation of the synthesis and turnover of estrogen and progesterone receptors, VMFC-0018, PI, UMC F21C, $72,600, 10%, annual recurring.

7. Prenatal effects on reproductive aging, Co-I (PI: F.S. vom Saal), UMC F21C Pilot Proj., $4920, 9-88 to 8-89.

8. Detection and isolation of dietary estrogens in animal feeds suspected of causing hyperestrogenism in swine and cattle, MO-00860, PI, CVM Anim. Health Form. Funds, $25,000, 5%, 1-89 to 12-90.

9. Special Equipment, scintillation counter upgrade, PI, UMC F21C, $3950, (equipment), 5-89.

10. Lithium-stimulated proliferation and phosphatidyl inositol metabolites, MOV-1-38, PI, CVM COR, $2803, 5%, 7-89 to 5-91.

11. Sex differences in brain uptake of steroids, Co-I (PI: F.S. vom Saal), UMC F21C Pilot Proj., $4985, 5-90 to 4-91.

12. Regulation of steroid receptor turnover in cancer cells, R29 CA50354, PI, NIH, $484,857, 50%, 8-90 to 7-95 (extended to 7-97).

13. Aging of the male reproductive system, DCB 9004806, Co-PI (PI: F.S. vom Saal), NSF, $150,000, 5%, 9-90 to 8-92.

14. NIH Small Instrumentation Grant, DHHS 1-S15-CA55976-01, PI, NIH, $5,000, 8-91 to 7-92.

15. Phosphatidylinositol metabolites as signals for proliferation in MCF-7 cells, MOV-1-62, PI, CVM COR, $4,000, 5%, 7-92 to 6-93.

16. Effects of estrogen on prostate function during aging, R01-AG08496, Co-I (PI: F.S. vom Saal), NIH, $543,000, 5%, 4-93 to 3-96.

17. Characterization of a hormone-independent, receptor-negative cell line isolated from MCF-7 human breast cancer cells and relation to tumor progression, MOV-1-69, PI, CVM COR, $4,000, 5%, 7-93 to 6-94.

18. NIH Small Instrumentation Grant, DHHS 1-S15-HL51352-01, PI, NIH, $6,334, 8-93 to 7-94.

19. Estrogenic actions of methoxychlor in urogenital sinus of fetal rats, Co-I (PI: F.S. vom Saal), UMC F21C Pilot Proj., $5000, 11-93 to 10-94.

20. Identification of a novel, non-nuclear form of estrogen receptors in MCF-7 human breast cancer cells, MOV-1-74, PI, CVM COR, $4,000, 2%, 7-94 to 6-95.

21. Proliferative signaling mechanisms in MCF-7 human breast cancer cells: the potential role of the ras-dependent MAP kinase signaling cascade, MOV-1-66, PI, CVM COR, $3,844, 2%, 7-94 to 6-95.

22. Regulation of estrogen receptors and estrogen responsiveness in human breast cancer cells, MO-VMFC0018, PI, University of Missouri AES, $103,200 annual, 10%, 3-1-95 to 2-28-00.

23. Characterization and localization of ovine luteal progesterone receptors, 9510851-1, Co-PI (PI: M.F. Smith), USDA NRI, $134,000, 5%, 9-1-95 to 8-31-97 (extended 8-31-99).

24. The role of estradiol in the etiology of prostate cancer: Prostate cancer in estrogen receptor-minus mice, Co-I (PI: D.B. Lubahn), Ellis Fischel Pilot Project, $30,000, 5%, 1-1-96 to 12-31-97.

25. Estrogen effects on breast tumor growth in estrogen receptor-minus mice, DAMD17-96-1-6055, Co-PI (PI: D.B. Lubahn), U.S. Army Breast Cancer Research Program, $149,995 ($51,350 1st year direct), 5%, 8-15-96 to 9-15-00.

26. Effects of endocrine disruptors on offspring, R01-ES08293, NIH, Co-PI (PI: F.S. vom Saal), $619,984 ($102,065 1st year direct), 5%, 7-15-96 to 6-30-00 (extended 6-30-01).

27. Environmental estrogen receptors in ER- mice, R01-ES08272, NIH, Co-PI (PI: D.B. Lubahn), $434,782 ($100,000 1st year direct), 5%, 8-1-96 to 7-31-00.

28. Prediction in vitro of the bioactivity of potential xenoestrogens in humans and animals, CMA7112, Chemical Manufacturers Association, PI, $134,938 ($92,430 1 year direct), 10%, 1-1-97 to 1-31-99.

29. Experimental assessment of environmental estrogens, FDA-222-97-2009(c), Office of Women's Health (OWH)/FDA, PI, $120,000 ($87,989 1 year direct), 7%, 9-26-97 to 1-31-99.

30. Methoxychlor and environmental "estrogen" receptors in ER-minus mice, R 825295, EPA, Co-PI (PI: D.B. Lubahn), $190,000 ($65,000 1st year direct), 7%, 2-10-97 to 2-9-99.

31. Breast cancer associated estrogen receptors: Catechol estrogen receptors in ER-minus mice, DAMD17-97-1-7171, US Army Breast Cancer Research Program, Co-PI (PI: D.B. Lubahn), $300,000 ($68,493 1st year direct), 10%, 9-1-97 to 10-1-00 (extended 10-1-01).

32. Do soy isoflavones provide protection against prostate cancer via a classical estrogen receptor-alpha (ER-alpha) independent mechanism? Comparison of ER-alpha-wild-type/TRAMP and double transgenic ER-alpha-knock-out/TRAMP mice, DAMD17-98-1-8529, US Army Prostate Cancer Research Program, Co-PI (PI: D.B. Lubahn), $470,996 ($125,000 1st year direct), 10%, 10-1-98 to 3-30-01.

33. Affinity column isolation of ligands for receptors of the steroid (nuclear) receptor superfamily: Estrogen receptor alpha, MOV-1-101, PI, CVM COR, $6,000, 5%, 7-1-99 to 6-30-01.

34. Mechanisms of estrogen responsiveness in human breast cancer cells, MO-VMFC0018, PI, University of Missouri AES, $111,650 annual, 10%, 3-2-00 to 2-28-05.

Active in 2001:

26, 31, 32, 33, 34

Pending [ top ]

A. Developmental Toxicity of Environmental Chemicals, NIH, Co-I (PI: F.S. vom Saal), $1,812,500 total/$1,250,000 direct ($362,500 1st year total/$250,000 1st year direct), 5%, 12-1-01 to 11-30-06.

B. An In Vitro Robotics Assay for Estrogenic Activity, NIH (SBIR to NIEHS), On-site Scientific Director (PI: C. Yang), $90,994 total/$61,317 direct, 10%, 1-1-02 to 6-30-02.

C. Plastic Baby Products Without Estrogenic Activity, NIH (SBIR to NIEHS), Collaborator (PI: C. Yang), $107,776 total/$72,625 direct, 5%, 1-1-02 to 6-30-02.

D. Food Antioxidants that are Free of Estrogenic Activity, NIH (SBIR to FDA), Collaborator (PI: C. Yang), $108,000 total/$72,000 direct, 5%, 1-1-02 to 6-30-02.

E. Integrated training in environmental hormone research, NIH, Co-I (PI: S. Swan), $1,089,838 total/$1,047,600 direct ($115,306 1st year total/$110,504 1st year direct), 5%, 6-1-02 to 5-31-07.

F. Effect of Soy Formula on Endocrine Function in Infants, USDA, Co-I (PI: L.S. Hillman), $175,000 ($75,000 1 year direct), 5%, 6-1-01 to 5-31-03.

Other [ top ]

Preliminary Invention Disclosure 93UMC016, University of Missouri, 9-30-92, "Cytotoxicity selective for human breast cancer cells," W.V. Welshons and G.E. Rottinghaus.

Awards and Honors [ top ]

NSF Predoctoral Fellowship, 1973-76
NIH Individual National Research Service Award, 1980-82
Honorary Member of the National Society of Phi Zeta, 1994

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