title: Involvement of transforming growth factor alpha (TGFalpha) and epidermal growth factor receptor (EGFR) in sex hormone-induced prostatic dysplasia and the growth of an androgen-independent transplantable carcinoma of the prostate.
abstract: We previously reported the induction of dysplasia, a putative precursor of carcinoma, in the dorsolateral prostates (DLPs) of Noble rats by the combined administration of testosterone (T) and estradiol-17beta (E2) for 16 weeks. Additionally, we demonstrated growth of the AIT, a DLP-derived, androgen-independent, transplantable solid tumor, in castrated syngeneic hosts. In this investigation, using Northern blot hybridization, radioimmunoassays and radioligand assays, we showed that transforming growth factor-alpha (TGFalpha) and epidermal growth factor receptor (EGFR) were expressed at close to non-detectable levels in the ventral prostates but at low, but measurable, levels in the DLPs of untreated rats. Enhanced expression of this ligand and its receptor was detected in the DLPs harboring dysplasia and marked overexpression of these molecules was noted in the AIT. In contrast, epidermal growth factor (EGF) expression was found to be constitutively expressed, at high levels, in both normal and dysplastic DLPs, but virtually absent in the AIT. Immunohistochemical data suggested that EGF, TGFalpha and EGFR were aprocine secretory products of the normal DLP, with TGFalpha and EGF localized to the supranuclear complexes and EGFR to the apical membranes of epithelial cells. Alterations in immunostaining patterns for TGFalpha and EGFR were exclusively detected in the dysplastic lesions in the DLPs of T + E2-treated rats. Enhanced intracytoplasmic localization for both peptides were found to accompany the loss of cell polarity in dysplastic foci. Strong intracytoplasmic immunostaining for TGFalpha was observed in some AIT cells whilst staining for EGFR was present in the membranes of tumor cells that formed psuedoacini. Taken together, our findings suggest that autocrine mechanisms may play an important role early in the carcinogenic process and that progression to an androgen-independent neoplastic growth may be modulated by this signaling pathway.
authors.affiliation: Department of Biology, Tufts University, Medford, Massachusetts, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Kaplan
authors.forename: I
authors.initials: I
authors.lastname: Leav
authors.forename: J
authors.initials: J
authors.lastname: Greenwood
authors.forename: P W
authors.initials: PW
authors.lastname: Kwan
authors.forename: S M
authors.initials: SM
authors.lastname: Ho
mesh_terms: D000818:Animals; D066246:ErbB Receptors / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D012739:Gonadal Steroid Hormones / Q000633:toxicity*; D008297:Male; D011230:Precancerous Conditions / Q000209:etiology*; D011471:Prostatic Neoplasms / Q000209:etiology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D016211:Transforming Growth Factor alpha / Q000032:analysis / Q000235:genetics / Q000502:physiology*
chemical_list: D012739:Gonadal Steroid Hormones; D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; D066246:ErbB Receptors