It has been suggested that normal prostate development, benign prostate hyperplasia (BPH), and prostate cancer development all require androgen/androgen receptor (AR) signaling in human and rodent. There are two types of cells, epithelial and stromal cells, constituting the prostate gland structure and mediating the physiological functions. The expression of AR in both epithelial and stromal cells may play important roles in controlling the homeostasis of prostate growth. Our recent data suggested that double stromal-cre ARKO (d-ARKO) mouse prostates have a profoundly reduced stromal AR function and impact on the homeostasis of prostate epithelial cells. We hypothesize that the AR in the stromal cells could play differential roles in benign prostate hyperplasia (BPH) and carcinogenesis. The reason we would like to compare stromal AR role in the BPH vs. cancer is that it will lead to more insights how stromal AR may differentially contribute to the etiology and progression of these two most commen prostate diseases in elder men. In the prostate field, even though there are available in vitro cell lines or tissue recombinant system to study stromal AR roles in normal prostate development, the kidney capture recombination system is grown in immune deficient mice without proper prostate microenvironment and can be only studied in 4-7 weeks. Therefore there is a lack of long-term in vivo model to investigate stromal AR impact on the BPH and prostate carcinogenesis. To date, there are still no suitable preclinical mouse models to study the stromal AR function. We propose to generate the double cre-ARKO (d-ARKO) for understanding the stromal AR role in development of BPH and carcinogenesis.
Three Specific Aims will be pursued.
Aim 1. To study the stromal AR role in BPH by crossing stromal d-ARKO mice with prolactin transgenic mice.
Aim 2. Generation of mouse models with stromal-fibroblast/smooth muscle selective double-cre AR knockout (d-ARKO) and investigation of prostate tumorigenesis and tumor progression.
Aim 3. Studying target gene and molecular mechanisms of stromal AR that could affect the epithelium during development of BPH and the prostate cancer. The accomplishment of the project will help us gain insights on the role of stromal AR in the prostate homeostasis and cancerous transformation and progression, and the results could also lead to developing new alternative treatments for BPH and prostate cancer in the future.

Public Health Relevance

To date, the epithelial androgen receptor (AR) has drawn a lot of attention in prostate carcinogenesis and there are thousands of publications focused on addressing the role of epithelial AR in prostate cancer. For the stromal AR, there is still a lack of an in vivo model to investigate its impact on the BPH and prostate carcinogenesis. The accomplishment of the studies could help to (i) uncover new insights about the cellular functions of stromal AR, (ii) explore and understand the critical roles of the stromal AR in BPH and prostate cancer initiation and progression, and (iii) could help to formulate new and alternative therapeutic strategies by selectively targeting stromal AR and its downstream pathways to battle those two important prostate diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA156700-04
Application #
8628080
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Mohla, Suresh
Project Start
2011-04-01
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
4
Fiscal Year
2014
Total Cost
$310,970
Indirect Cost
$109,695
Name
University of Rochester
Department
Pathology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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Shen, Jiliang; Lin, Hui; Li, Gonghui et al. (2016) TR4 nuclear receptor enhances the cisplatin chemo-sensitivity via altering the ATF3 expression to better suppress HCC cell growth. Oncotarget 7:32088-99
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