Enhanced induction of prostatic dysplasia and carcinoma in Noble rat model by combination of neonatal estrogen exposure and hormonal treatments at adulthood.
Estrogens have been implicated to play certain but yet undefined roles in the normal and neoplastic growth of prostate gland. Studies of perinatal exposure in rodents demonstrate that effects of perinatal estrogenization are permanent and carcinogenic in prostate gland. In the Noble (Nb) rat model, prostatic dysplasia and neoplastic lesions can be induced by a chronic treatment with both testosterone and estrogen at adulthood. However, by this conventional protocol, neoplastic lesions are mostly confined to the lateral (LP) and ventral (VP) prostates, while gross prostatic tumors are rarely induced. Based on these two experimental models, we developed a modified treatment protocol for the enhancement of prostate cancer induction in Nb rat model by combining neonatal estrogen exposure of male offspring followed by the hormonal treatment at adulthood (NeoE + T-E2). Using this modified protocol, we were able to induce more extensive development of neoplastic lesions in all three prostatic lobes and also gross tumors at relatively high incidence within 6-9 months. Western blottings and immunohistochemistry showed that ERalpha expression was increased in the hypertrophic peri-acinar and -ductal smooth muscle cells while ERbeta and AR expressions are markedly decreased in dysplastic and neoplastic lesions in NeoE + T-E2-treated prostates. Immunohistochemistry showed that expression of three tumor suppressors (BRCA2, PTEN, and Rap1) and tubulin-alpha are markedly decreased in dysplastic and neoplastic lesions. In addition, loss of expression of smooth muscle differentiation markers (desmin, alpha-actin, and vinculin) and defects of basement membranes were also seen in the reactive stroma. These results suggest that exposure to high levels of estrogens, either endogenous or exogenous, in early life could play a role in the development of prostate cancer in later life.
Yuen
Mong-Ting
MT
Department of Anatomy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, P.R. China.
Leung
Lai-Kwok
LK
Wang
Jun
J
Wong
Yong-Chuan
YC
Chan
Franky L
FL
D000199:Actins / Q000032:analysis; D000818:Animals; D000831:Animals, Newborn; D024682:BRCA2 Protein / Q000032:analysis; D015153:Blotting, Western; D003893:Desmin / Q000032:analysis; D004054:Diethylstilbestrol / Q000008:administration & dosage / Q000633:toxicity; D047628:Estrogen Receptor alpha / Q000032:analysis; D047629:Estrogen Receptor beta / Q000032:analysis; D004967:Estrogens / Q000008:administration & dosage* / Q000633:toxicity; D004968:Estrogens, Non-Steroidal / Q000008:administration & dosage / Q000633:toxicity; D005260:Female; D007150:Immunohistochemistry; D007279:Injections, Subcutaneous; D007797:Laminin / Q000032:analysis; D008297:Male; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000032:analysis; D011247:Pregnancy; D011467:Prostate / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011944:Receptors, Androgen / Q000032:analysis; D013997:Time Factors; D014404:Tubulin / Q000032:analysis; D016596:Vinculin / Q000032:analysis; D020827:rap1 GTP-Binding Proteins / Q000032:analysis
D000199:Actins; D024682:BRCA2 Protein; D003893:Desmin; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D004968:Estrogens, Non-Steroidal; D007797:Laminin; D011944:Receptors, Androgen; D014404:Tubulin; D016596:Vinculin; D004054:Diethylstilbestrol; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat; D020827:rap1 GTP-Binding Proteins