Androgenic regulation of growth factor and growth factor receptor expression in the CWR22 model of prostatic adenocarcinoma.
The effects of androgen manipulation on epidermal growth factor (EGF) receptor, p185erbB-2 and transforming growth factor-alpha (TGF-alpha) levels were examined in prostatic adenocarcinoma. Male nude mice were inoculated with the CWR22 androgen-dependent human prostatic tumor or an androgen-independent (CWR22R) derivative. Mice with CWR22 tumors were castrated and subsequently killed at 3, 7, 21, 28 or 42 days post-castration. Other CWR22-bearing mice received s.c. testosterone pellets at 21 days post-castration and were killed 7 days later. EGF receptor, p185erbB-2 and TGF-alpha levels were examined by immuno-histochemistry. Strong EGF receptor and p185erbB-2 immunostaining was detected in CWR22 tumors from intact controls. EGF receptor immunostaining decreased by 65% to 70% at 21 to 42 days post-castration. Testosterone treatment at 21 to 28 days post-castration resulted in a 2-fold increase in EGF receptor immunostaining. p185erbB-2 immunostaining within CWR22 tumors did not decrease following castration and, in fact, was slightly increased at 7 days post-castration. The effects of castration on EGF receptor and p185erbB-2 levels were confirmed by Western blot analysis. Fewer than 10% of CWR22 tumor cells demonstrated strong TGF-alpha immunostaining, and androgen manipulation did not effect TGF-alpha immunostaining. In contrast, 30% of androgen-independent CWR22R tumor cells were strongly immunostained for TGF-alpha. Our findings indicate that EGF receptor levels, but not p185erbB-2 levels, are strongly dependent on testosterone in CWR22 tumors. The co-localization of TGF-alpha and the EGF receptor in CWR22R tumors suggests that these factors may constitute an autocrine pathway that regulates androgen-independent growth.
Department of Pathology, University of Alabama at Birmingham, 35233-0007, USA.
R B
RB
Myers
D
D
Oelschlager
U
U
Manne
P N
PN
Coan
H
H
Weiss
W E
WE
Grizzle
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000187:drug effects*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D016211:Transforming Growth Factor alpha / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000728:Androgens; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D016211:Transforming Growth Factor alpha