Expression of estrogen receptor beta in the fetal, neonatal, and prepubertal human prostate
Biochemistry & Molecular Pharmacology
Graduate School of Biomedical Sciences; Department of Pathology; Department of Surgery; Department of Surgery, Division of Urology
Life Sciences | Medicine and Health Sciences
BACKGROUND: Although androgens have long been implicated in the development, regulation, and pathophysiology of the prostate, evidence suggests that estrogens may also affect these processes. Specifically, estrogens have been shown to influence the development of the fetal and neonatal rodent prostate and to induce a pathognomonic change, termed squamous metaplasia, in the developing and adult prostate. Studies have been inconclusive, however, as to whether estrogens enhance or restrain the growth of the gland. Although the fetal rodent prostate has been reported to contain both estrogen receptor alpha (ER-alpha) and beta (ER-beta), there have been no reports as to whether either of the ER subtypes is expressed in the developing human prostate.
METHODS: In the present study, we used a novel antibody, directed against a unique sequence in the F domain of ER-beta, and laser capture microdissection/reverse transcriptase-polymerase chain reaction to study the expression of the receptor in the fetal, neonatal, and prepubertal human prostate. Results were compared with the expression of ER-alpha, androgen receptor (AR), prostatic acid phosphatase (PAP), prostate specific antigen (PSA), high molecular weight cytokeratin (HMCK), and the proliferative marker Ki67.
RESULTS: For the first time, we report that ER-beta is the only estrogen receptor detected at the protein level in the morphologically normal developing human fetal prostate. By midgestation, strong immunostaining for ER-beta was detected in the nuclei of nearly 100% of epithelial and in the majority of stromal cells. This pattern of expression was evident in the fetal, neonatal, and early prepubertal prostate. However, by 11 years postnatal, staining for the receptor became restricted primarily to the basal epithelial and stromal compartments, a pattern analogous to that observed in the normal adult gland. ER-alpha mRNA was present in microdissected stroma of the fetal gland. Although ER-alpha was not immunodetected in any morphologically normal fetal epithelial or stromal cells, weak staining for the receptor, however, was found in some examples of squamous metaplasia, suggesting the role of alpha-subtype in this lesion. ER-alpha was clearly visualized immunohistochemically at 1 month of postnatal development where it was then localized exclusively in periacinar stromal nuclei, which suggests that it may exert paracrine influences on further prostatic glandular development. Interestingly, the expression of ER-beta early in prostatic development occurred coincident with both the increasing rate of epithelial cell proliferation, observed in the first half of gestation, and the reported high levels of estrogen in the gland from midgestation until term. Paradoxically, however, staining for the receptor remained intense, despite the dramatic decrease in Ki67 labeling observed in the second half of gestation.
CONCLUSION: Our results indicate that the effects of estrogens on the growth of the human fetal prostate are mediated primarily by ER-beta but that ER-alpha contributes to postnatal glandular development. Furthermore, these results suggest that ER-beta, possibly in concert with androgens, may mediate diverse effects on prostate epithelial proliferation by first promoting cell expansion early in gestation, and then acting to limit growth later in prostatic development.
DOI of Published Version
Prostate. 2002 Jun 1;52(1):69-81. Link to article on publisher's site
Adams, Jason Y.; Leav, Irwin; Lau, Kin-Mang; Ho, Shuk-Mei; and Pflueger, Solveig M.V., "Expression of estrogen receptor beta in the fetal, neonatal, and prepubertal human prostate" (2002). GSBS Student Publications. 37.