Age-dependent alterations in sex hormone milieu, tissue oxidant status, and inflammation are purported endogenous risk factors of human prostate cancer (PCa). Treatment of Noble rats, a human PCa-relevant model, with testosterone (T) and estradiol-17beta (E2) for 16 weeks induced epithelial dysplasia, a proliferative lesion that resembles human prostatic intraepithelial neoplasia (PIN), in the lateral prostates (LPs), but not in the ventral prostate (VPs) of treated rats. The LP dyslasia is frequently attended by inflammation and resembles the human proliferative inflammatory atrophy (PIA), a putative precursor to PIN and PCa. Longer treatment of rats with T causes PCa exclusively in the LPs of 100 percent of the treated rats. T treatment also causes hyperprolactinemia, which induces inflammation in the LP. Marked oxidative stress (OS)- and nitrative stress (NS)-related damages, aberrant expression of cyclooxygenase-2 (COX-2), NAD(P)H oxidases (NOXs), and NO synthases (NOSs), as well as disruption of anti-oxidant defenses were noted in the dysplastic LPs. We here hypothesize that T-supported E2 action contributes to early neoplastic development directly in rat LP by induction of chronic OS/NS that ultimately leads to tumorigenesis. Moreover, the, E2-induced hyperprolactinemia activates tissue inflammatory responses that inflict additional OS/NS damages, thus exacerbating the process.
Three aims are proposed.
Aim I - To determine if T+ E2 induced LP dysplasia is accompanied by induction of OS/NS directly in the prostatic epithelial compartment and that this process is exacerbated by the presence of inflammation. Laser-capture-microscopy will be used to sample normal and dysplastic epithelia, and their adjacent stroma, in areas with and without evidence of inflammation, to assess the hormone- induced versus inflammation-mediated OS/NS-associated changes. Five types of biomarkers will be evaluated: 1) disruption of OS/NS generation/defense pathways, 2) OS/NS-induced lipid, DNA and protein damages, 3) altered expression of T+E2 induced oncogenes, 4) imbalances in cell proliferation and apoptosis, 5) production of inflammation mediators via COX and/or lypoxygenase (LOX) pathways.
Aim 2 - To determine if combined celecoxib (a specific COX-2 inhibitor) and zileuton (a 5-LOX inhibitor) treatment negates or diminishes inflammation and/or dysplasia in the LPs of T+E2 treated rats and if this effect is attended by diminution of OS/NS-associated biomarkers.
Aim 3 - Using a LP organ culture system, we will further elucidate the direct cancer-promoting actions of E2, T, DHT, and PRL, in the absence of inflammation or systemic confounding factors.
Aim 4 -To determine whether advancement of age renders the rat prostate more susceptible to hormone-induced inflammation and/or carcinogenesis. Results from our studies should help explicate the relation between inflammation and carcinogenesis in the human prostate, a topic of intense debate.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA112532-04
Application #
7618496
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Poland, Alan P
Project Start
2006-07-01
Project End
2012-05-31
Budget Start
2009-06-01
Budget End
2012-05-31
Support Year
4
Fiscal Year
2009
Total Cost
$264,562
Indirect Cost
Name
University of Cincinnati
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Lam, Hung-Ming; Ho, Shuk-Mei; Chen, Jing et al. (2016) Bisphenol A Disrupts HNF4?-Regulated Gene Networks Linking to Prostate Preneoplasia and Immune Disruption in Noble Rats. Endocrinology 157:207-19
Ho, Shuk-Mei; Tam, Neville Ngai Chung (2015) Organoid model shows effect of BPA on prostate development. Nat Rev Urol 12:658-9
Tam, Neville Ngai-Chung; Zhang, Xiang; Xiao, Hong et al. (2015) Increased susceptibility of estrogen-induced bladder outlet obstruction in a novel mouse model. Lab Invest 95:546-60
Ho, Shuk-Mei; Johnson, Abby; Tarapore, Pheruza et al. (2012) Environmental epigenetics and its implication on disease risk and health outcomes. ILAR J 53:289-305
Ouyang, Bin; Baxter, C Stuart; Lam, Hung-Ming et al. (2012) Hypomethylation of dual specificity phosphatase 22 promoter correlates with duration of service in firefighters and is inducible by low-dose benzo[a]pyrene. J Occup Environ Med 54:774-80
Tang, Wan-yee; Morey, Lisa M; Cheung, Yuk Yin et al. (2012) Neonatal exposure to estradiol/bisphenol A alters promoter methylation and expression of Nsbp1 and Hpcal1 genes and transcriptional programs of Dnmt3a/b and Mbd2/4 in the rat prostate gland throughout life. Endocrinology 153:42-55
Isaac, Jared; Tarapore, Pheruza; Zhang, Xiang et al. (2012) Site-specific S-nitrosylation of integrin ?6 increases the extent of prostate cancer cell migration by enhancing integrin ?1 association and weakening adherence to laminin-1. Biochemistry 51:9689-97
Leung, Yuet-Kin; Lee, Ming-Tsung; Lam, Hung-Ming et al. (2012) Estrogen receptor-beta and breast cancer: translating biology into clinical practice. Steroids 77:727-37
Wu, T; Giovannucci, E; Welge, J et al. (2011) Measurement of GSTP1 promoter methylation in body fluids may complement PSA screening: a meta-analysis. Br J Cancer 105:65-73
Ho, Shuk-Mei; Lee, Ming-Tsung; Lam, Hung-Ming et al. (2011) Estrogens and prostate cancer: etiology, mediators, prevention, and management. Endocrinol Metab Clin North Am 40:591-614, ix

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