Estradiol suppresses tissue androgens and prostate cancer growth in castration resistant prostate cancer

Abstract

Background: Estrogens 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.

Methods: The human CRPC xenograft LuCaP 35V was implanted into orchiectomized male SCID mice and established tumors were treated with placebo, 17beta-estradiol or 17beta-estradiol and estrogen receptor antagonist ICI 182,780. Effects of 17beta-estradiol on tumor growth were evaluated and tissue testosterone (T) and dihydrotestosterone (DHT) evaluated by mass spectrometry.

Results: Treatment of LuCaP 35V with 17beta-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 17beta-estradiol (p = 0.03). The addition of the estrogen receptor antagonist ICI 182,780 did not significantly change survival or growth. 17beta-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 17beta-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.

Conclusions: CRPC in anorchid animals maintains tumoral androgen levels despite castration. 17beta-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.

Figure 1

Effect of 17β-estradiol or 17β-estradiol combined with ICI 182,780 on human CRPC xenograft growth in SCID mice. Castrated SCID male mice were implanted with LuCaP 35V castration resistant cells and when tumors reached 150-400 mm³, treated with placebo pellets (n = 10): 17β-estradiol by subcutaneous pellets (n = 10); or 17β-estradiol pellets and ICI 182,780 (5 mg/kg SC once per week) as detailed in Materials and Methods. Data shown are Kaplan-Meier estimates of survival for tumor bearing animals treated with indicated agents.

Figure 2

Androgen levels in LuCaP prostate cancer human prostate cancer xenografts grown in castrate and intact SCID mice. Testosterone and DHT levels were measured by mass spectrometry in castration sensitive (CS) and castration resistant variants of the LuCaP 35 xenograft. The castration resistant tumors were treated with agents as indicated (Fig. 1 and Materials and Methods). Androgen levels were also evaluated in liver tissue obtained from each set of treated castrate animals. Data represent three tissue samples per data point; bars, SE.