I started to study androgen receptor (AR) functions in prostate cancer in Lirim Shemshedini lab (University of Toledo) during my Ph.D.. In this period of study, I mainly focused on the roles of AR coactivators and AR target genes in prostate cancer (PCa). I have published the results on studying the cooperative role of c-Jun on AR transactivation and the roles of AR regulated SGC?1, ETV1, and MRP4 genes in PCa. After I received my Ph.D., I joined Steven Balk lab at Beth Israel Deaconess Medical Center (BIDMC)/Harvard Medical School. This Cancer Biology Program is administratively housed within the Hematology-Oncology Division, which comprises a large faculty involved in patient care, clinical, translational, and basic cancer research. Research in the Balk lab is focused on PCa and AR, and the lab has funding from multiple sources including NIH R01 support, a Prostate Cancer SPORE, and DoD Prostate Cancer program sources. In the lab, I continued to study the roles of AR in the lethal form of PCa that develops the resistance to androgen deprivation therapy (ADT). This form of cancer is called castration resistant prostate cancer, or CRPC. My initial study is focusing on AR regulation by HER signaling, and then I moved to the field of studying TMPRSS2:ERG fusion gene in PCa. Using fusion positive cell lines, I have established xenograft models that clearly mimic the progression of CRPC. Studying this model led to two major findings: (1) increased intratumoal androgen synthesis that mediates tumor resistance to ADT and CYP17A1 inhibition;(2) increased AR expression in CRPC is due to AR suppression of its own gene. AR plays a pivotal role in primary PCa and regains its functions in CRPC. In contrast to the well- established AR activation function on gene transcription, its suppression function is poorly understood. This proposal mainly focuses on elucidating the molecular mechanisms of AR mediated gene transcriptional repression. My immediate goal of 2-yrs mentored phase will be to pursue the molecular basis and clinical relevance of AR mediated its own gene expression through binding of its intron 2 site (ARBS2) and repressing the gene transcription. Several other AR-repressed gene loci that mediate expression of androgen synthetic genes (HSD17B6 and AKR1C3) will also be studied. In particularly, the repressor complex on chromatin and their actions that results in the epigenetic modifications on ARBS2 and regulates its activity will be identified. More important, any distinct mechanism that separates AR as an activator versus a repressor needs to be elucidated. These findings will also be translated into clinical therapy to enhance the activity of ARBS2 but not affect AR activated gene loci. For the long-term goal, which includes the 3-yr independence phase, the findings on AR gene loci will be extended to the whole genome of PCa cells. Taking the advantages of next generation sequencing and bioinformatics analysis on high throughput data, the global AR-mediated suppressor elements will be identified in PCa cells and their functions will also be studied. Moreover, the global roles of AR interacted repressor complex on gene transcription and on prostate cancer initiation and progression will also be studied in the phase of proposal. Current findings clearly demonstrate that we do not yet fully understand how AR functions, and that further novel mechanisms of action may contribute to its regulation of subsets of genes. As AR regulates a large number of genes involved in many cellular pathways, the potential ability to selectively target subsets of these genes has broad implications for the therapy of PCa and other diseases.

Public Health Relevance

In this proposal, we are trying to elucidate the molecular mechanisms behind the novel suppression function of androgen receptor (AR) that mediates transcriptional repression on a subset of genes, which are involved in DNA synthesis and proliferation in prostate cancer. We propose that androgen deprivation therapy, which is standard for treating prostate cancer patients, may relive AR suppression of this subset of genes and result in relapse of more aggressive form of cancer, called castration resistant prostate cancer (CRPC). Therefore, distinct mechanisms of AR activation versus suppression on gene transcription make it possible to selectively augment AR transcriptional repressor function and thereby prevent or delay the emergence of CRPC.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Career Transition Award (K99)
Project #
5K99CA166507-02
Application #
8533770
Study Section
Special Emphasis Panel (ZCA1-RTRB-K (J1))
Program Officer
Schmidt, Michael K
Project Start
2012-08-17
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$134,946
Indirect Cost
$9,996
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Ma, Fen; Ye, Huihui; He, Housheng Hansen et al. (2016) SOX9 drives WNT pathway activation in prostate cancer. J Clin Invest 126:1745-58
Gao, Shuai; Ye, Huihui; Gerrin, Sean et al. (2016) ErbB2 Signaling Increases Androgen Receptor Expression in Abiraterone-Resistant Prostate Cancer. Clin Cancer Res 22:3672-82
Hsieh, Chen-Lin; Botta, Ginevra; Gao, Shuai et al. (2015) PLZF, a tumor suppressor genetically lost in metastatic castration-resistant prostate cancer, is a mediator of resistance to androgen deprivation therapy. Cancer Res 75:1944-8
Chen, Eddy J; Sowalsky, Adam G; Gao, Shuai et al. (2015) Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors. Clin Cancer Res 21:1273-80
Yu, Ziyang; Chen, Sen; Sowalsky, Adam G et al. (2014) Rapid induction of androgen receptor splice variants by androgen deprivation in prostate cancer. Clin Cancer Res 20:1590-600
Yuan, X; Cai, C; Chen, S et al. (2014) Androgen receptor functions in castration-resistant prostate cancer and mechanisms of resistance to new agents targeting the androgen axis. Oncogene 33:2815-25
Cai, Changmeng; He, Housheng Hansen; Gao, Shuai et al. (2014) Lysine-specific demethylase 1 has dual functions as a major regulator of androgen receptor transcriptional activity. Cell Rep 9:1618-1627
Yu, Ziyang; Cai, Changmeng; Gao, Shuai et al. (2014) Galeterone prevents androgen receptor binding to chromatin and enhances degradation of mutant androgen receptor. Clin Cancer Res 20:4075-85
Chen, Sen; Jiang, Xinnong; Gewinner, Christina A et al. (2013) Tyrosine kinase BMX phosphorylates phosphotyrosine-primed motif mediating the activation of multiple receptor tyrosine kinases. Sci Signal 6:ra40
Liu, Feiyang; Zhang, Xin; Weisberg, Ellen et al. (2013) Discovery of a Selective Irreversible BMX Inhibitor for Prostate Cancer. ACS Chem Biol :

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