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The Introduction of the Taiwanese Osteoporosis Society President's Award For Dr. Chawnshang Chang

The Taiwanese Osteoporosis Society’s highest honor, the "President’s Award -Scholar of the Year" for 1999 is presented to Chawnshang Chang, Ph.D., George Hoyt Whipple Distinguished Professor and Director of the George Whipple Laboratory for Cancer Research from the University of Rochester.

Dr. Chawnshang Chang has established himself as a leader in the field of Sex Hormones through his pioneering studies on the molecular mechanism of the androgen receptor and its biological functions. His accomplishments over the past 10 years have included the cloning of the androgen receptor, the discovery of the TR2 and TR4 orphan receptors and many androgen receptor coactivators. The studies of these receptors and coactivators have clinical applications to androgen-related diseases.

Chawnshang grew up in Taiwan, receiving his Bachelor of Science degree from the National Taiwan University in 1978. Like many students before him, he made the trip across the Pacific Ocean to enter graduate school in the U.S., and earned his Ph.D. degree from the University of Chicago in 1985. As Professor Shutsung Liao’s student, he cloned and characterized two androgen target genes. The first was Glutathione S-transferase, which represented the first isolated androgen-repressed gene (JBC, 1987) and the second was Spermine-binding protein, the first isolated androgen early-response gene (JBC, 1987). With this solid training in cloning techniques and the encouragement from his mentor, Dr. Liao, he remained as a post doctorate fellow in Dr. Liao’s lab to investigate what was the biggest challenge in the field of Andrology; the cloning of the androgen receptor. In 1988, Chawnshang succeeded in becoming the first scientist to clone the complete human and rat androgen receptors. (Science, 1988; PNAS, 1988). He then applied recombinant techniques to overexpress a large quantity of androgen receptor and used it to produce the first monoclonal antibody to the androgen receptor (Endo., 1989). The successful cloning of the androgen receptor and the generation of the first androgen receptor monoclonal antibody was not only truly groundbreaking, but also represented one of the most important contributions in the field of Andrology.

Since that initial publication in Science in 1988, more than 1000 papers have been published on the subject of androgen receptor, and research made possible by Chawnshang’s androgen receptor sequence continues to have an impact in the field today. The cloning of the androgen receptor eventually led to the identification of the genetic basis of two important diseases: Testicular Feminization Syndrome (Mol. Endo., 1993) and Kennedy’s Disease, also known as Spinal/Bulbar Muscular Atrophy (JBC, 1999). The development of an immunoassay for the androgen receptor and the discovery of androgen receptor mutations in prostate tumor also provided great insight into the progression of prostate cancer and its change from an androgen-dependent to an androgen-independent stage (Endo., 1990).

During the cloning of the androgen receptor, Chawnshang unexpectedly found another cDNA clone with a sequence similar to other members of the steroid receptor superfamily. Since all known steroid receptors (estrogen, progesterone, glucocorticoid, and mineralocorticoid) had been cloned, Chawnshang named this new member of the steroid receptor superfamily as Testicular Receptor 2 (TR2), one of the first identified nuclear orphan receptors.

After initial skepticism, Chawnshang convinced his colleagues in the nuclear receptor field that there may be more receptors than those previously identified and TR2 eventually received public notice in 1988 (BBRC, 1988). With the completion of the C. elegans Genome Project, today’s scientists have found more than 300 similar receptor sequences. These surprising findings suggest our knowledge about the steroid receptor field could still be very limited at this time. Nevertheless, the pioneer cloning of the first nuclear orphan receptor, TR2, still represents a landmark discovery in the field of steroid receptors.

Over the next 10 years, Chawnshang’s Lab identified another orphan receptor, TR4 (PNAS, 1994), and has established TR2 and TR4 as transcriptional regulators, which also control many important endocrine pathways. These pathways include retinoids, Vitamin D, thyroid hormone, the peroxisome proliferator activated receptor, ciliary neurotrophic factor, and erythropoietin. TR2 and TR4 also regulate viral gene expression in HIV, HPV, HBV, and SV40. In recent findings, it was discovered that TR2 and TR4 could function as repressors, through heterodimerization with androgen receptor or estrogen receptor, to inhibit androgen and estrogen signal pathways. Conversely, the androgen receptor and the estrogen receptor can also function as repressors to inhibit the TR2/TR4 signal pathways (PNAS, 1999). These unexpected findings have expanded the classical view that the androgen receptor and the estrogen receptor act only as receptor/transcription factors to regulate their own target genes. Through the heterodimerization with TR2 or TR4, the androgen receptor and estrogen receptor are now known to regulate a distinct new category of target genes, which cannot be regulated by the androgen or estrogen receptor alone. Also, for the first time, he demonstrated that an orphan receptor, such as TR2 or TR4, can function as a repressor to inhibit the function of sex hormone receptors.

After holding a two-year Junior Faculty position at Ben May Institute and the Department of Surgery/Urology at the University of Chicago, Chawnshang was recruited in 1990 by the University of Wisconsin-Madison as an Assistant Professor in the Department of Human Oncology and the Comprehensive Cancer Center. While there, he was quickly promoted to Associate Professor (1993) and then Full Professor (1996). At the same time, he also served as the Director for the Tissue and Blood Bank in the UW Cancer Center, which collected patients’ blood and tissues for clinical studies. This valuable experience later helped Chawnshang to pay very close attention to the linkage of his fundamental research to clinical relevance, observations, and problems. This period at UW-Madison (1990-1997) was very productive. More than 100 papers were published in various prestigious journals. The isolation of the first androgen receptor coactivator ARA70 (PNAS, 1996) and several additional coactivators (ARA24, ARA54, ARA55, ARA160, and the tumor suppressors, Rb and BRCAI) represent another key discovery in the Andrology field. The impact of these discoveries are enormous, they not only proved that the maximal or proper androgen activity requires more than just the androgen receptor, but also demonstrated that the specificity of sex hormones or antiandrogens can be modulated by some selective androgen receptor coactivators.

Based on these discoveries, Chawnshang was able to show that 17b-estradiol, the natural female hormone, but not synthetic estrogens such as DES, can activate androgen target genes, providing the first evidence to link the female hormone to the male hormone receptor signaling pathway (PNAS, 1998). More importantly, Chawnshang was able to apply the coactivator’s functions to explain why flutamide, an antiandrogen used widely in prostate cancer therapy, may become an androgenic compound to stimulate androgen target genes (Lancet, 1997; PNAS, 1998). This finding has very important clinical implications; it not only helps us to explain the failure of androgen ablation therapy, but may also provide us with the opportunity to screen for potential new drugs that can still maintain their antiandrogenic activity in the presence of androgen receptor and coactivators.

The discovery of androgen receptor coactivators has also successfully contributed to an understanding of how other signaling pathways, such as Her2/Neu, IL-6, MAP Kinase, P13-Kinase, and Akt Kinase, can stimulate or repress prostate cancer cell growth. In Chawnshang’s recent findings, he demonstrates that the reason these growth factors can modulate androgen receptor transcriptional activity is that growth factors may allow the androgen receptor to differentially recruit coactivators by phosphorylation of androgen receptor at some specific amino acids (PNAS, 1999). This important finding may eventually allow scientists to develop the drugs to block the growth factor-mediated prostate cancer growth by prevention of the interaction between androgen receptor and androgen receptor coactivators.

Chawnshang was also able to demonstrate that D5-androstenediol, a precursor of testosterone, is a natural hormone with androgenic activity which can be enhanced by selective androgen receptor coactivators (PNAS, 1998). The prostate cancer patients’ serum D5-androstenediol remains high during androgen ablation therapy, and flutamide can not block the D5-androstenediol-mediated AR transcriptional activity completely. Therefore, the development of new drugs to block D5-androstenediol’s androgenic activity in the presence of androgen receptor coactivators, may become a very important step in the treatment of prostate cancer (PNAS, 1999).

Chawnshang accepted the Directorship of the George Whipple Laboratory for Cancer Research at the University of Rochester in 1997 and additional appointments in the Departments of Pathology, Urology, Radiation Oncology, and the Cancer Center. He proceeded to build strong research teams with focus on the androgen receptor along with androgen-related diseases such as prostate cancer, osteoporosis, and baldness. Chawnshang also established a new Ph.D. program in Molecular Oncology in 1997 and continues to serve as its director today.

Chawnshang’s ties to the Taiwan Academy are also very strong. He is very well known and respected among young students in Taiwan. Since 1990, more than 20 students from Taiwan have either graduated from or are being trained in his Lab. In addition, many other students were able to enter Ph.D. programs within the U.S. through his recommendations and personal help. Many of his students have gone on to become faculty members at Universities and have kept in close communication or formed collaborations with his Lab. Recently, Chawnshang extended his collaboration with Taiwan by accepting a Co-Directorship and Visiting Professorship at the Chang-Gung University, where he is helping to set up a new institution to be called "Reproductive Medicine". This new institution’s focus will be on sex hormone in women’s diseases such as breast and ovarian cancers, as well as osteoporosis. With his experience in the establishment of the George Whipple Laboratory for Cancer Research at the University of Rochester, Chawnshang is able to provide very valuable suggestions for this new Institute, such as laboratory design, equipment purchasing, personnel training, and recruitment of faculty/staff members. He also helped to establish strong collaborative projects between this new Institute and various Institutes in the U.S. to accelerate the progression, recognition, and reputation of this new Institute in the sex hormone field.

Chawnshang’s leadership and enthusiasm have also led him to be a very popular speaker and organizer for symposia in the field of steroid receptor signaling and sex hormone related diseases, such as prostate cancer. He has given more than 200 speeches during the last 10 years in the U.S. and other countries.

In addition to these outstanding records and scientific achievements, one of Chawnshang’s more salient characteristics as a researcher in the sex hormone field is his generosity. More than 700 labs in the world have been using his free gifts of cDNAs, antibodies and proteins to androgen receptor androgen receptor coactivators, and TR2/TR4 orphan receptors, to study the sex hormone-related topics. His interest and commitment to help other colleagues in many Labs has earned him the reputation of "Mr. Generosity in Andrology".

As a true leader in the field of sex hormone receptors, it is not surprising that Chawnshang has won numerous awards for his pioneering work with the androgen receptor. These include the "Ayerst Award" from the American Endocrine Society, the "Outstanding Young Faculty Award" from the Andrew Melon Foundation, the "Jieping Wu Award" from the Chinese Urology Association, the "Davey Memorial Award for Outstanding Cancer Research" from the University of Rochester, and the "President Award" from the Taiwan Urology Association. He was only the second ever non-Japanese recipient to be named as an Honorable-Fellow of the Japanese Andrology Society and one of the few scientists to obtain six awards from the CaPCURE Foundation for his outstanding research in prostate cancer.

To add to these achievements, the Taiwanese Osteoporosis Society is very proud to present the "Scholar for 1999 Award" to Dr. Chawnshang Chang in recognition of his distinguished career and contributions in the sex hormone receptor field.