Estrogen induces apoptosis in a rat prostatic adenocarcinoma: association with an increased expression of TGF-beta 1 and its type-I and type-II receptors.
Rats transplanted with the androgen-sensitive Dunning R3327 PAP prostatic adenocarcinoma were castrated and treated with either estrogen or vehicle alone for short periods (4 hr, 12 hr, 24 hr) and for 6 weeks. In these tumors the expression of TGF-beta 1, TGF-beta type-I and type-II receptors (TGF-beta RI, TGF-beta RII) was examined by immunohistochemistry. Apoptotic cells were identified by in situ nick and labelling (TUNEL). Tumor growth was retarded by castration and even more by additive estrogen treatment. The epithelium of the untreated tumors stained weakly for TGF-beta 1 and TGF-beta RI, but TGF-beta RII was not detected. Castration induced moderate TGF-beta 1 immunoreactivity in a major part of the glandular epithelium after 24 hr. After 12 hr already, castration plus estrogen resulted in an intense staining for TGF-beta 1 in the basal epithelial cells, some of which also showed an apoptotic appearance. The percentage of cells having stained positive for TGF-beta 1 was significantly higher in the estrogen-treated groups than in the castrated group after 12 hr, and its elevated TGF-beta 1 level remained at 6 weeks. Notably, the increased immunoexpression of TGF-beta 1 occurred before the onset of induction of apoptosis. In parallel with the upregulation of TGF-beta 1 after castration, the expression of its receptors. TGF-beta RI and RII, was induced and was further enhanced by the additive estrogen treatment. The number of intensely stained TGF-beta 1 tumor cells showed a strong correlation with the number of apoptotic tumor cells identified by TUNEL in the whole material. Furthermore, TGF-beta 1 immunoreactivity co-localized with the presence of apoptotic cells in the estrogen-treated tumors at 6 weeks after castration.
Landström
M
M
Department of Pathology, University of Umeà, Sweden.
Eklöv
S
S
Colosetti
P
P
Nilsson
S
S
Damber
J E
JE
Bergh
A
A
Funa
K
K
D030201:Activin Receptors, Type I; D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry; D008297:Male; D008940:Mitotic Index / Q000187:drug effects; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D051381:Rats; D011916:Rats, Inbred F344; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*
D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D004958:Estradiol; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625843:Tgfbr1 protein, rat