2008 Faculty Researchers

Dennis B. Lubahn, PhD

Finding new functions for hormones, receptor proteins and genes: a molecular genetics approach to exploring the roles of estrogens, phytoestrogens, and estrogen receptors in human disease, particularly prostate cancer

---

Department

Biochemistry and Child Health

Office Location

110A ASRC

Phone #:

Office: (573) 884-6781
Fax: (573) 882-7748

Summary

One of the long term goals of my research program is to find novel functions for both estrogens and estrogen response proteins, and then to identify the molecular mechanisms mediating these functions. This research will lead to a better understanding of estrogens' developmental, physiological, and biochemical roles in humans, and additionally will add to our general understanding of how endogenous estrogens and estrogenic chemicals in the environment can impinge upon human health. To pursue these research goals, we "knocked out" the estrogen receptor (ER) gene in mice via homologous recombination and asked the following question: Would an ER-minus mouse, which lacked the classic fu1llength ER protein, respond to any known estrogen, estrogen metabolite, or exogenous (natural, like phytoestrogens, or synthetic) estrogen analog? IfER-minus mice did respond, then we would know that at least one estrogen response protein other than ER exists. The working hypothesis was that several non-ER response proteins exist and that in transgenic ER-minus mice we would see a response to some estrogens. We decided to test the phytoestrogen, genistein, and other additional phytoestrogens, either as pure compounds or as part of complex herbal extracts for their ability to affect prostate cancer progression in the TRAMP prostate cancer mouse model in ERaKO and wild type genetic backgrounds. We have found that genistein requires ERa to exert its protective effects suggesting that the estrogen receptor is important in prostate cancer treatments by other phytoestrogens as well. ERbKO TRAMP and double ERalERBKO mice will also be tested with several other potential anti-carcinogenic compounds found in herbal medicines to see ifthere are additional non-ERa molecular pathways for phytoestrogen action in cancer therapy. Other phytoestrogens and their plant source to be tested in these transgenic models both individually as pure chemicals and in complex mixtures with other compounds and plant extracts include these reported traditional cancer therapies:

1. Ginkgo Biloba (Quercetin); 2. Scuttlaria Biacalensis (Baicalein); 3- Chamomile German Flower (Apigenin), 4- Soy isoflavone (Genistein); 5- Yucca roots (Resveratrol); 6- Turmeric roots (Curcumin) 7- Sencha green tea leaves (Epigallocatechin Gallate). Today, there is no doubt that estrogens playa central role in human pathology, where its importance in cancer, as well as sexual maturation, reproduction, osteoporosis, diabetes, and cardiovascular disease is known although poorly understood The question that we can now answer is: Which estrogens/phytoestrogens working through which receptors are involved in these important disease processes? For now we are focusing on the effects of phytoestrogens in prostate cancer.

Selected references:

1. Alteration of Reproductive Function but not Prenatal Sexual Development after Insertional Disruption of the Mouse Estrogen Receptor Gene, Lubahn, D.B., Moyer, J.S., Golding, T.S., Couse, J.F., Korach, K.S., & Smithies, O. Proceedings of the National Academy of Sciences USA 90 11162-11166 (1993).
2. Estrogen Resistance Caused by a Mutation in the Estrogen-Receptor Gene in a Man, Smith, E.P., Boyd, J., Frank, G.R, Takahashi, H., Cohen, RM., Specker, B., Williams, T.c., Lubahn, D.B., & Korach, K.S. New England Joumal of Medicine 3311056¬61(1994).
3. Dietary genistein increased DMBA-induced mammary adenocarcinoma in wild-type, but not ER alpha KO, mice. Day JK. Besch-Williford C. McMann TR Hufford MG. Lubahn DB. MacDonald RS. Nutrition and Cancer-An International Journa1. 39:226-232, (2001).
4. Phytoestrogens in Common Herbs Regulate Prostate Cancer Cell Growth in Vitro. Nader S. Shenouda, Christine Zhou, Jimmy D. Browning, Pete J. Ansell, Mary S. Sakla, Dennis B. Lubahn, and Ruth S. MacDonald. Nutrition and Cancer, International Journa1. 49 (2): 200-208 (2004).