Abstract
BackgroundEstrogens suppress tumor growth in prostate cancer which progresses despite anorchid serum androgen levels, termed castration resistant prostate cancers (CRPC), although the mechanisms are unclear. We hypothesize that estrogen inhibits CRPC in anorchid animals by suppressing tumoral androgens, an effect independent of the estrogen receptor.MethodsThe human CRPC xenograft LuCaP 35V was implanted into orchiectomized male SCID mice and established tumors were treated with placebo, 17β-estradiol or 17β-estradiol and estrogen receptor antagonist ICI 182,780. Effects of 17β-estradiol on tumor growth were evaluated and tissue testosterone (T) and dihydrotestosterone (DHT) evaluated by mass spectrometry.ResultsTreatment of LuCaP 35V with 17β-estradiol slowed tumor growth compared to controls (tumor volume at day 21: 785 ± 81 mm3 vs. 1195 ± 84 mm3, p = 0.002). Survival was also significantly improved in animals treated with 17β-estradiol (p = 0.03). The addition of the estrogen receptor antagonist ICI 182,780 did not significantly change survival or growth. 17β-estradiol in the presence and absence of ICI 182,780 suppressed tumor testosterone (T) and dihydrotestosterone (DHT) as assayed by mass spectrometry. Tissue androgens in placebo treated LuCaP 35V xenografts were; T = 0.71 ± 0.28 pg/mg and DHT = 1.73 ± 0.36 pg/mg. In 17β-estradiol treated LuCaP35V xenografts the tissue androgens were, T = 0.20 ± 0.10 pg/mg and DHT = 0.15 ± 0.15 pg/mg, (p < 0.001 vs. controls). Levels of T and DHT in control liver tissue were < 0.2 pg/mg.ConclusionsCRPC in anorchid animals maintains tumoral androgen levels despite castration. 17β-estradiol significantly suppressed tumor T and DHT and inhibits growth of CRPC in an estrogen receptor independent manner. The ability to manipulate tumoral androgens will be critical in the development and testing of agents targeting CRPC through tissue steroidogenesis.
Highlights
Estrogens suppress tumor growth in prostate cancer which progresses despite anorchid serum androgen levels, termed castration resistant prostate cancers (CRPC), the mechanisms are unclear
Effect of estradiol on tumor growth in orchiectomized mice Previous studies have shown that 17β-estradiol suppresses tumor growth in ovariectomized mice bearing prostate cancer xenografts LuCaP 35, LuCaP 49, LuCaP 58, LuCaP 73, and LNCaP [13]
The current study demonstrates that estradiol slows tumor progression of CRPC xenografts grown in orchiectomized mice
Summary
Estrogens suppress tumor growth in prostate cancer which progresses despite anorchid serum androgen levels, termed castration resistant prostate cancers (CRPC), the mechanisms are unclear. We have previously shown that 17β-estradiol suppressed CRPC growth and delayed mortality in multiple castration resistant xenograft models in vivo [13]. In these castrate animals, estrogen suppressed tumor growth despite the lack of circulating testosterone, dehydroepiandrosterone (DHEA) and androstenedione synthesis, a feature resulting from a lack of CYP17 in murine adrenal glands [14]. Elevated tumoral androgens were associated with increased tumor transcripts encoding enzymes involved in the synthesis of androgens [18] These studies suggested that prostate cancer can maintain intratumoral androgens to aid in tumor progression in CRPC. In the current study we hypothesize that 17β-estradiol might inhibit CRPC growth in anorchid hosts and suppress tumoral androgens by competitively inhibiting steroidogenesis from cholesterol, and reduce available tumoral androgens that drive growth [19,20,21,22]
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