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.

See Dr. Chang's full publication list under Whipple Laboratory.

Yang L, Wang L, Lin HK, Kan PY, Xie S, Tsai MY, Wang PH, Chen YT, and Chang C. 2003. Interleukin-6 differentially regulates androgen receptor transactivation via PI3K-Akt, STAT3, and MAPK, three distinct signal pathways in prostate cancer cells. Biochem Biophys Res Commun. Jun 6;305(3):462-499.

Cai Y, Dai T, Ao Y, Konishi T, Chuang KH, Lue Y, Chang C, and Wan YJ. 2003. Cytochrome P450 genes are differentially expressed in female and male hepatocyte retinoid X receptor alpha-deficient mice. Endocrinology. 2003 Jun;144(6):2311-2318.

Hsu CL, Chen YL, Yeh S, Ting HJ, Hu YC, Lin H, Wang X, and Chang C. 2003. The use of phage display technique for the isolation of androgen receptor interacting peptides with (F/W)XXL(F/W) and FXXLY new signature motifs. J Biol Chem. 2003 Jun 27;278(26):23691-23698.

Rahman MM, Miyamoto H, Lardy H, and Chang C. 2003. Inactivation of androgen receptor coregulator ARA55 inhibits androgen receptor activity and agonist effect of antiandrogens in prostate cancer cells. Proc Natl Acad Sci U S A. Apr 29;100(9):5124-5129.

Miyamoto H, Marwah P, Marwah A, Lardy H, and Chang C. 2003. 3 beta-acetoxyandrost-1,5-diene-17-ethylene ketal functions as a potent antiandrogen with marginal agonist activity. Proc Natl Acad Sci U S A. Apr 15;100(8):4440-4444.

Rahman MM, Miyamoto H, Takatera H, Yeh S, Altuwaijri S, and Chang C. 2003. Reducing the Agonist Activity of Antiandrogens by a Dominant-negative Androgen Receptor Coregulator ARA70 in Prostate Cancer Cells. J Biol Chem. May 30;278(22):19619-19626.

Lee DK, and Chang C. 2003. Molecular communication between androgen receptor and general transcription machinery. J Steroid Biochem Mol Biol. Jan;84(1):41-49. [Review]

Thin TH, Wang L, Kim E, Collins LL, Basavappa R, and Chang C. 2003. Isolation and characterization of androgen receptor mutant, AR(M749L), with hypersensitivity to 17-beta estradiol treatment. J Biol Chem. Feb 28;278(9):7699-7708.

Heinlein CA, and Chang C. 2002. Androgen Receptor (AR) Coregulators: An Overview. Endocr Rev Apr;23(2):175-200.

Ting HJ, Yeh S, Nishimura K, and Chang C. 2002. Supervillin associates with androgen receptor and modulates its transcriptional activity. Proc Natl Acad Sci U S A Jan 22;99(2):661-666.

Lin HK, Yeh S, Kang HY, Chang C. 2001. Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Proc Natl Acad Sci U S A Jun 19;98(13):7200-7205.

Heinlein CA, Chang C. 2001. Role of chaperones in nuclear translocation and transactivation of steroid receptors. Endocrine Mar;14(2):143-149.

Kang HY, Lin HK, Hu YC, Yeh S, Huang KE, and Chang C. 2001. From transforming growth factor-beta signaling to androgen action: Identification of Smad3 as an androgen receptor coregulator in prostate cancer cells. Proc Natl Acad Sci U S A. Mar 13;98(6):3018-3023

Mantalaris A, Panoskaltsis N, Sakai Y, Bourne P, Chang C, Messing EM, and Wu JH. 2001. Localization of androgen receptor expression in human bone marrow. J Pathol. Mar;193(3):361-366.

Lee DK, Duan HO, and Chang C. 2001. Androgen Receptor Interacts with the Positive Elongation Factor P-TEFb and Enhances the Efficiency of Transcriptional Elongation. 2001. J. Biol. Chem., Vol. 276, Issue 13, 9978-9984, March 30.

Hsiao, P.W. and Chang, C. 1999. Isolation and characterization of ARA160 as the first androgen receptor N-terminal-associated coactivator in human prostate cells. J. Biol. Chem. 274(32):22373-22379.

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.

Links are to the PubMed publication list. PubMed is maintained by the National Library of Medicine and provides complete abstracts of publications,
as well as links to the full text of many articles (at journal homepages).