Chawnshang Chang
George Hoyt Whipple Professor of Pathology & Laboratory Medicine, Oncology, and Urology
Ph.D. 1988 (University of Chicago)

Website:George Whipple Lab for Cancer Research

E-Mail: Chang@urmc.rochester.edu

      Since cloning androgen receptors (AR) (Science, 1988), finding the first AR coactivators (PNAS, 1996) and their linkage in prostate cancer (Lancet, 1997), and generation the first tissue- specific knockout AR mouse via cre-lox system (PNAS, 2002). Our laboratory has continued to focus on the study of molecular mechanisms of steroid hormone function, especially androgen action in prostate, testis, breast and brain. The lab goals are to study the physiological functions of AR in various target organs, to elucidate the mechanisms of how prostate cancer progresses from an androgen-dependant to an androgen-independent stage, and also develop the new antiandrogene without progression into antiandrogen withdrawal syndrome.The following summarizes our current AR research efforts from FIVE different directions:

1.	How does AR interact with transcriptional factors to regulate their target genes and how do other coregulators interact with AR to modulate target gene expression at the translation/transcription levels?
2.	Purification/crystallization of AR and AR coregulators and their use in screening antiandrogens.
3.	How can we identify T- or DHT-specific target genes and develop T- or DHT- specific antiandrogens?
4.	How can we clone AR-associated proteins and, from them, develop new types of antiandrogens by inhibiting the interaction of AR and ARAs?
5.	Generation and characterization of individual tissue-specific knockout mouse to study AR in vivo functions in (a) prostate/breast/liver/bladder cancers, (b) immune system, (c) male& female fertility, (d) baldness/acne and (e) brain-neuron.

For the orphan nuclear TR2/TR3/TR4 receptors that our Lab cloned, we will concentrate on the following topics:

1.	Identifying new ligands/hormones for TR2/TR3/TR4.
2.	Finding physiological roles of these ligands/hormones in proliferation, differentiation, and apoptosis.
3.	Studying the potential role of these ligands/hormones in resistance to radiation and chemo-therapeutic drugs
4.	Studying the bi-directional regulation between orphan receptors and (a) brain neuro-systems, (b) vitamin A and D systems, and (c) p53 tumor suppressors.
5.	Studying TR2/TR4 physiological roles in TR2/TR4 knock-out mice and in TR2/TR4-overexpressing transgenic mice.

In summary, by combining basic and clinical studies of androgen receptors and orphan nuclear receptors, we hope to develop a better understanding of androgen mechanisms and produce better antiandrogens leading to more effective drug therapies in the near future.

Miyamoto H, Messing EM, Chang C.> 2005. Does androgen deprivation improve treatment outcomes in patients with low-risk and intermediate-risk prostate cancer? Nat Clin Pract Oncol. May;2(5):236-237.

Yang L, Xie S, Jamaluddin MS, Altuwaijri S, Ni J, Kim E, Chen YT, Hu YC, Wang L, Chuang KH, Wu CT, Chang C. 2005. Induction of Androgen Receptor Expression by Phosphatidylinositol 3-Kinase/Akt Downstream Substrate, FOXO3a, and Their Roles in Apoptosis of LNCaP Prostate Cancer Cells. J Biol Chem. Sep 30;280(39):33558-65

Miyamoto H, Altuwaijri S, Cai Y, Messing EM, Chang C. 2005. Inhibition of the Akt, cyclooxygenase-2, and matrix metalloproteinase-9 pathways in combination with androgen deprivation therapy: potential therapeutic approaches for prostate cancer. Mol Carcinog. Sep;44(1):1-10. Review.

Wang L, Hsu CL, Chang C. 2005. Androgen receptor corepressors: an overview. Prostate. May 1;63(2):117-130. Review.

Chuang KH, Lee YF, Lin WJ, Chu CY, Altuwaijri S, Wan YJ, Chang C. 2005. 9-cis-retinoic acid inhibits androgen receptor activity through activation of retinoid X receptor. Mol Endocrinol. May;19(5):1200-1212

Collins LL, Lee YF, Heinlein CA, Liu NC, Chen YT, Shyr CR, Meshul CK, Uno H, Platt KA, Chang C. 2004. Growth retardation and abnormal maternal behavior in mice lacking testicular orphan nuclear receptor 4. Proc Natl Acad Sci U S A. Oct 19;101(42):15058-15063.

Hu YC, Wang PH, Yeh S, Wang RS, Xie C, Xu Q, Zhou X, Chao HT, Tsai MY, and Chang C. 2004. Subfertility and defective folliculogenesis in female mice lacking androgen receptor. Proc Natl Acad Sci U S A. Aug 3;101(31):11209-14. Epub 2004 Jul 26.

Lin HK, Hu YC, Lee DK, and Chang C. 2004. Regulation of Androgen Receptor Signaling by PTEN Tumor Suppressor Through Distinct Mechanisms in Prostate Cancer Cells. Mol Endocrinol. Jun 17 [Epub ahead of print]

Chang C, Chen YT, Yeh SD, Xu Q, Wang RS, Guillou F, Lardy H, and Yeh S. 2004. Infertility with defective spermatogenesis and hypotestosteronemia in male mice lacking the androgen receptor in Sertoli cells. Proc Natl Acad Sci U S A. May 4;101(18):6876-81. Epub 2004 Apr 23.

Yeh, S., Miyamoto, H., Shima, H. and Chang, C. 1998. From estrogen to androgen receptor: a new pathway for sex hormone in human prostate. Proc. Natl. Acad. Sci. U S A , 95:5527-5532.

Chang, C., Kokontis, J., and Liao, S. 1988. Molecular cloning of human and rat complementary DNA encoding androgen receptors. Science, 240:324-326.