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Endocrinology |
and ER-ß in Normal and Malignant Prostatic Epithelial Cells: Regulation by Methylation and Involvement in Growth Regulation1
Division of Urology, Department of Surgery, University of Massachusetts Medical School, Worcester, Massachusetts 01655 [K-M. L., S-M. H.], Department of Biology, Tufts University, Medford, Massachusetts 02155 [K-M. L., M. L.] and Urological Clinic, New England Medical Center, Boston, Massachusetts 02111 [J. L.]
The aim of the current study is to demonstrate normal and malignant
prostatic epithelial cells (PrECs) as targets for receptor-mediated
estrogenic and antiestrogenic action. Using an improved protocol, we
have successfully isolated and maintained highly enriched populations
of normal PrECs from ultrasound-guided peripheral zone biopsies,
individually determined to be morphologically normal. Semiquantitative
reverse transcription-PCR analyses were used to determine whether
transcripts of estrogen receptor (ER)-
and those of ER-ß were
expressed in our normal PrEC primary cultures, in a commercially
available PrEC preparation (PrEC; Clontech), in an immortalized PrEC
line established from a benign prostatic hyperplasia specimen (BPH-1),
and in three prostatic cancer cell lines (LNCaP, PC-3, and DU145).
Expression levels of ER- and ER-ß transcripts were related to
those of two estrogen-responsive genes [progesterone receptor (PR) and
pS2], at the message levels, to gain insights into the functionality
of the ER subtypes in PrECs. Interestingly, only transcripts of ER-ß,
but not those of ER-, were found in our primary cultures of normal
PrECs, along with both PR and pS2 mRNA. These data strongly suggest
that estrogen action was signaled exclusively via ER-ß in normal
human PrECs. In contrast, PrEC (Clontech) and BPH-1 cells expressed
both ER- and ER-ß transcripts and no PR nor pS2 mRNA in PrEC and
only a minimal level of PR mRNA in BPH-1. Among the three prostate
cancer cell lines, LNCaP expressed ER-ß mRNA along with transcripts
of PR and pS2, DU145 expressed messages of ER-ß and PR, and PC-3
cells exhibited ER-, ER-ß, and pS2 mRNA. Thus, unlike normal
PrECs, expression patterns of these genes in malignant PrECs are more
variable.
Treatment of prostate cancer cells with demethylation agents
effectively reactivated the expression of ER- mRNA in LNCaP and
DU145 and that of pS2 message in DU145. These findings provide
experimental evidence that ER- gene silencing
in prostate cancer cells, and perhaps also in normal PrECs, are caused
by DNA hypermethylation.
To evaluate the potential of using antiestrogens as prostate cancer therapies, we have assessed the growth-inhibitory action of estrogens (estradiol and diethylstilbestrol) and antiestrogens (4-hydroxy-tamoxifen and ICI-182,780) on PC-3 and DU-145 cells. In PC-3 cells, which express both ER subtypes, estrogens as well as antiestrogens are effective inhibitors. In contrast, in DU145 cells, which express only ER-ß, antiestrogens, but not estrogens, are growth inhibitors. By comparison, ICI 182,780 is the more effective cell growth inhibitor. Importantly, the ICI 182,780-induced antiproliferative effects were reversed by cotreatment of DU145 cells with an ER-ß antisense oligonucleotide, hence lending additional support to a central role played by ER-ß in mediating growth-inhibitory action of antiestrogens.
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D. Pasquali, V. Rossi, D. Esposito, C. Abbondanza, G. A. Puca, A. Bellastella, and A. A. Sinisi Loss of Estrogen Receptor {beta} Expression in Malignant Human Prostate Cells in Primary Cultures and in Prostate Cancer Tissues J. Clin. Endocrinol. Metab., May 1, 2001; 86(5): 2051 - 2055. [Abstract] [Full Text]
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A. Latil, I. Bièche, D. Vidaud, R. Lidereau, P. Berthon, O. Cussenot, and M. Vidaud Evaluation of Androgen, Estrogen (ER{{alpha}} and ER{beta}), and Progesterone Receptor Expression in Human Prostate Cancer by Real-Time Quantitative Reverse Transcription-Polymerase Chain Reaction Assays Cancer Res., March 1, 2001; 61(5): 1919 - 1926. [Abstract] [Full Text]
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