Estradiol suppresses tissue androgens and prostate cancer growth in castration resistant prostate cancer.
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.
Department of Medicine, University of Washington School of Medicine, 1959 NE Pacific St, Seattle, WA, USA. rbmontgo@u.washington.edu
Bruce
B
Montgomery
Peter S
PS
Nelson
Robert
R
Vessella
Tom
T
Kalhorn
David
D
Hess
Eva
E
Corey
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D013196:Dihydrotestosterone / Q000378:metabolism*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D000077267:Fulvestrant; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D016513:Mice, SCID; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism*; D013997:Time Factors; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
D018931:Antineoplastic Agents, Hormonal; D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D013196:Dihydrotestosterone; D000077267:Fulvestrant; D013739:Testosterone; D004958:Estradiol