The prostate gland is a hormone dependent tissue regulated throughout life by androgen action. It is also known that estrogens play key roles in prostate development and homeostasis and contribute to prostate carcinogenesis and progression. While estrogen actions through multiple receptors have been studied in detail in female organs, the mechanisms of estrogenic effects in the prostate gland are not well understood. Recently, our laboratory demonstrated that human prostate epithelial stem and progenitor cells from normal adult prostates express robust levels of estrogen receptors - ER?, ER? and GPR30 - and exhibit increased proliferative responses to estradiol-17?. Further, preliminary data indicate heightened ER expression in human prostate cancer (PCa) stem-like cells suggesting that this minor tumor cell population may be a direct estrogen target. The overall goal of the proposed studies is to delineate the roles of estrogen receptors (ER?, ER? and GPR30) in epithelial stem and progenitor cells of the normal and cancerous human prostate gland and to elucidate their specific roles in promoting or preventing carcinogenesis and progression.
Three Specific Aims are proposed to accomplish these goals.
AIM 1 : Define the specific roles for ER?, ER? and GPR30 in regulating self-renewal, amplification, apoptosis and/or differentiation in human prostate stem- progenitor cells from normal adult tissues. To accomplish this, we will utilize a fully characterized prostasphere system to interrogate stem and progenitor cells from primary prostate epithelial cultures of disease-free organ donors.
AIM 2 : Elucidate the expression and roles of specific ERs in human prostate cancer stem-like cells. Primary epithelial cultures of benign and PCa cells from patient specimens will be utilized to enrich for stem/progenitor cells by prostasphere assay. Results will be supported by interrogating ER actions in two immortalized human PCa stem-like cell lines, HPET and HuSLC. Co-culture studies with normal and cancer- associated fibroblasts will be used to define the estrogen-responsive stem cell niche in normal and cancerous human prostates.
AIM 3 : Delineate the actions of specific ERs in mediating hormonal carcinogenesis in vivo and regulating PCa growth and progression. An in vivo cell recombination graft model has been established using normal human prostate stem/progenitor cells or human PCa stem-like cells mixed with embryonic mesenchyme to generate chimeric prostate-like tissues with normal human prostate epithelium or prostate cancer. Targeted ER knockdown and selective estrogen receptor modulators (SERMs) will be tested to delineate estrogen actions and regulate PCa growth in vivo. Together, the present approaches will provide the first direct evidence for ER-specific actions in human prostate stem and progenitor cells. Importantly, use of fresh human prostate specimens from organ donors and PCa patients will grant translational relevance to the findings. The detailed molecular results supported by in vivo responses of prostate cancer growth to SERMs have potential to identify new therapeutic targets for management of PCa and inform future drug discovery strategies using novel small molecules that target stem cell ER actions.
Emerging evidence indicates a central role for estrogens in prostate health and disease. The goals of the present proposal are to elucidate the precise roles of estrogen receptors recently found in normal human prostate stem and progenitor cells and in human prostate cancer stem- like cells. These studies have potential to identify estrogen receptors as direct therapeutic targets for management of prostate diseases in human such as benign prostatic hyperplasia (BPH) and prostate cancer.
|Denyer, Steven; Bhimani, Abhiraj D; Papastefan, Steven et al. (2018) Magnetic kyphoplasty: A novel drug delivery system for the spinal column. PLoS One 13:e0201402|
|Prins, Gail S; Patisaul, Heather B; Belcher, Scott M et al. (2018) CLARITY-BPA academic laboratory studies identify consistent low-dose Bisphenol A effects on multiple organ systems. Basic Clin Pharmacol Toxicol :|
|Rinaldi, J C; Santos, S A A; Colombelli, K T et al. (2018) Maternal protein malnutrition: effects on prostate development and adult disease. J Dev Orig Health Dis 9:361-372|
|Hu, Wen-Yang; Hu, Dan-Ping; Xie, Lishi et al. (2017) Isolation and functional interrogation of adult human prostate epithelial stem cells at single cell resolution. Stem Cell Res 23:1-12|
|Nanjappa, M K; Medrano, T I; Prins, G S et al. (2017) Transdifferentiation of adult rat stem Leydig cells into prostatic and uterine epithelium, but not epidermis. Andrology 5:1165-1173|
|Prins, Gail S; Ye, Shu-Hua; Birch, Lynn et al. (2017) Prostate Cancer Risk and DNA Methylation Signatures in Aging Rats following Developmental BPA Exposure: A Dose-Response Analysis. Environ Health Perspect 125:077007|
|Cooke, Paul S; Nanjappa, Manjunatha K; Ko, CheMyong et al. (2017) Estrogens in Male Physiology. Physiol Rev 97:995-1043|
|Sharif, Asma; Malhotra, Neha R; Acosta, Andres M et al. (2017) The Development of Prostate Adenocarcinoma in a Transgender Male to Female Patient: Could Estrogen Therapy Have Played a Role? Prostate 77:824-828|
|George, Jitu W; Patterson, Amanda L; Tanwar, Pradeep S et al. (2017) Specific deletion of LKB1/Stk11 in the Müllerian duct mesenchyme drives hyperplasia of the periurethral stroma and tumorigenesis in male mice. Proc Natl Acad Sci U S A 114:3445-3450|
|Dambal, Shweta; Baumann, Bethany; McCray, Tara et al. (2017) The miR-183 family cluster alters zinc homeostasis in benign prostate cells, organoids and prostate cancer xenografts. Sci Rep 7:7704|
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