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Androgenic regulation of growth factor and growth factor receptor expression in the CWR22 model of prostatic
R B Myers1, D Oelschlager, U Manne
1Department of Pathology, University of Alabama at Birmingham, 35233-0007, USA.
Abstract:
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.
Insights
Testosterone significantly impacts epidermal growth factor (EGF) receptor levels in prostate cancer tumors. Androgen manipulation affected EGF receptor but not p185erbB-2 levels, suggesting a key role in tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Endocrinology
Background:
- Prostatic adenocarcinoma growth is often regulated by androgens.
- Epidermal growth factor (EGF) receptor and related signaling molecules play roles in cell proliferation and cancer.
- Understanding the interplay between androgens and growth factor signaling is crucial for prostate cancer treatment.
Purpose of the Study:
- To investigate the effects of androgen manipulation on key signaling molecules in prostate cancer.
- To examine the expression of EGF receptor, p185erbB-2, and TGF-alpha in response to androgen deprivation and replacement.
Main Methods:
- Utilized CWR22 androgen-dependent and CWR22R androgen-independent human prostate tumor xenografts in male nude mice.
- Employed castration and testosterone pellet implantation to manipulate androgen levels.
- Assessed protein levels using immunohistochemistry and Western blot analysis.
Main Results:
- EGF receptor levels in CWR22 tumors significantly decreased after castration and increased with testosterone treatment.
- p185erbB-2 levels showed minimal change with castration and were not significantly affected by androgen manipulation.
- Transforming growth factor-alpha (TGF-alpha) levels were largely unaffected by androgen manipulation in CWR22 tumors but were elevated in androgen-independent CWR22R tumors.
Conclusions:
- Testosterone strongly influences EGF receptor expression in androgen-dependent prostate cancer.
- EGF receptor, not p185erbB-2, is a key mediator of androgen effects in CWR22 tumors.
- Co-localization of TGF-alpha and EGF receptor in CWR22R tumors suggests a potential autocrine pathway driving androgen-independent growth.