Delay of postnatal maturation sensitizes the mouse prostate to testosterone-induced pronounced hyperplasia: protective role of estrogen receptor-beta.
The role of estrogens in the etiology of prostate cancer is controversial. To demonstrate the specific effects of estrogens and androgens on the development of the prostatic epithelial hyperplasia, we used luteinizing hormone receptor knockout mice (LuRKO), which are resistant to pituitary regulation mediated by luteinizing hormone, lack postnatal androgen production, and have rudimentary accessory sex glands, the growth of which can be induced with exogenous androgen replacement. This model is thus ideal for the investigation of direct hormonal effects on the prostate. Testosterone, but not 5alpha-dihydrotestosterone, replacement from 21 days of life for 8 weeks induced pronounced hyperplasia and inflammation in the prostates of LuRKO mice. Interestingly, 5alpha-dihydrotestosterone combined with 17beta-estradiol did not induce hyperplasia or inflammation, and treatments with inhibitors of estrogen action, aromatase inhibitor, and ICI 182780 further exacerbated testosterone-induced hyperplastic growth. However, the activation of estrogen receptor (ER)-beta with a specific agonist, DPN [2,3-bis(4-hydroxyphenol)-propionitrile], prevented the development of prostatic hyperplasia and inflammation in testosterone-treated LuRKO mice. Thus, it seems that in the presence of sufficient androgenic stimulation, it is the balance between ER-alpha- and ER-beta-mediated signaling that determines whether estrogens promote hyperplasia or protect the prostate against hyperplastic changes.
Savolainen
Saija
S
Functional Foods Forum, University of Turku, Turku, Finland.
Pakarainen
Tomi
T
Huhtaniemi
Ilpo
I
Poutanen
Matti
M
Mäkelä
Sari
S
D000818:Animals; D047072:Aromatase Inhibitors / Q000378:metabolism; D013196:Dihydrotestosterone / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism; D004965:Estrogen Antagonists / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism*; D000077267:Fulvestrant; D006801:Humans; D006965:Hyperplasia; D007249:Inflammation / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009570:Nitriles / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011388:Prolactin / Q000378:metabolism; D011467:Prostate / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism; D011974:Receptors, LH / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014230:Triazoles / Q000378:metabolism; D011422:Propionates
D047072:Aromatase Inhibitors; D013196:Dihydrotestosterone; D004958:Estradiol; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D000077267:Fulvestrant; D019394:Ki-67 Antigen; D009570:Nitriles; D010750:Phosphoproteins; D011388:Prolactin; D011944:Receptors, Androgen; D011974:Receptors, LH; D011980:Receptors, Progesterone; D013739:Testosterone; D015534:Trans-Activators; D014230:Triazoles; C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D011422:Propionates; C486419:Trp63 protein, mouse; C111409:finrozole