We have shown recently that simultaneous administration of testosterone (T) and estradiol-17Beta (E2) to intact Noble (Nb) rats for 16 wk induces intraductal dysplasia exclusively in the dorsal prostate (DP). Others have reported a significant number of these dysplasias subsequently evolve into invasive carcinoma. This sex hormone-induced lesion of Nb rats closely resembles ductal dysplasia in the human gland which is believed to be the antecedent lesion of prostatic carcinoma. While others report that the lesion can be induced by chronic treatment of rats with aromatizable T or estrone, per se, we have been unable to cause dysplasia following separate chronic treatment of animals with pharmacological doses of non-aromatizable 5Alpha-dihydrotestosterone (DHT) or E2. Therefore, our goal will be to determine if the pathogenesis of dysplasia can be linked to direct hormonal interactions of androgen-estrogen, or whether development of the pre-neoplastic lesion requires androgen-supported activation of estrogen to potentially carcinogenic metabolites; eg catechols. To investigate the role of estrogen in the genesis of dysplasia, we will utilize steroids with differing biological potencies and binding affinities for estrogen receptor (ER), and which differ in their capacity to form catechols. These estrogens will be administered for 16 wk to Nb rats, alone or in combination with DHT. Alterations in androgen-supported ER status and/or catechol formation in DP and hepatic microsomes will be assayed at varying time intervals during treatment. Temporal perturbations in specific biochemical parameters will be correlated with alterations in mitotic indices, and with hormone-mediated changes in differentiation found in the evolving dysplastic lesions. Our multidisciplinary studies will involve androgen and estrogen metabolism, receptor assays, immunohistochemistry, electron microscopy, and pathology. Our studies will be of particular importance to understanding critical factors involved in the pathogenesis of human prostatic carcinoma since sex steroids have long been suspected of playing a major role in the initation and progression of this neoplasm. The induction of dysplasia by combinations of E2 and T in our Nb rat model is of particular interest since imbalances in circulating sex steroids which could favor estrogen action at the target organ have been reported in agging men and in individuals with prostatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA015776-15
Application #
3164280
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1978-09-30
Project End
1993-09-29
Budget Start
1992-04-01
Budget End
1993-09-29
Support Year
15
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Tufts University
Department
Type
Schools of Veterinary Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02111
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
Cheong, Ana; Zhang, Xiang; Cheung, Yuk-Yin et al. (2016) DNA methylome changes by estradiol benzoate and bisphenol A links early-life environmental exposures to prostate cancer risk. Epigenetics 11:674-689
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
Leung, Yuet-Kin; Chan, Queeny Kwan-Yi; Ng, Chi-Fai et al. (2014) Hsa-miRNA-765 as a key mediator for inhibiting growth, migration and invasion in fulvestrant-treated prostate cancer. PLoS One 9:e98037
Lee, Ming-Tsung; Ouyang, Bin; Ho, Shuk-Mei et al. (2013) Differential expression of estrogen receptor beta isoforms in prostate cancer through interplay between transcriptional and translational regulation. Mol Cell Endocrinol 376:125-35
Lee, Ming-Tsung; Leung, Yuet-Kin; Chung, Irving et al. (2013) Estrogen receptor ? (ER?1) transactivation is differentially modulated by the transcriptional coregulator Tip60 in a cis-acting element-dependent manner. J Biol Chem 288:25038-52
Lee, Ming-Tsung; Ho, Shuk-Mei; Tarapore, Pheruza et al. (2013) Estrogen receptor ? isoform 5 confers sensitivity of breast cancer cell lines to chemotherapeutic agent-induced apoptosis through interaction with Bcl2L12. Neoplasia 15:1262-71
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
Lam, Hung-Ming; Suresh Babu, C V; Wang, Jiang et al. (2012) Phosphorylation of human estrogen receptor-beta at serine 105 inhibits breast cancer cell migration and invasion. Mol Cell Endocrinol 358:27-35

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