Estrogen has been used for the treatment of prostate cancer since the early 1940s.3 It is generally believed this action is indirectly mediated at the hypothalamic level to suppress the circulating androgens.4 However, in the early 1960s, a direct action of estrogen via their own receptors in the prostate was proposed by Mangan et al.5 Recently, the evidences that ER expressed in normal prostate, benign prostatic hyperplasia (BPH), prostate cancer specimens, and different prostate cancer cell lines, along with the demonstration of the stimulatory or inhibitory effects of estrogen on prostate cancer cells growth suggested estrogen may exert direct effects on prostate via their own receptors.6-11 The following sections will discuss the distribution of ERa and ERp in prostate tissues, cancer specimens, and cancer cell lines.
Both ERa and ERp express in the human prostate tissue.2'12 In normal prostate tissue ERa is mostly expressed in stromal cells with occasional expression in the basal epithelial cells,8,11,13-15 whereas ERp is abundantly present in basal epithelial cells.8,11,13 The complementary location of both ERa and ERp might explain why some early studies reported ERa in both the stroma and epithelium of the normal prostate, which may be caused by cross reaction against both ER subtypes.16
In BPH, ERa immunostaining could not be detected in several studies.15,16 Using enzyme immunoassay, Mobbs et al. (1990) found high positivity of ERa in BPH.17 The latter immunostaining studies found ERa was stronger in BPH than in normal prostates and localized in both epithelial and stromal cells.8 Immunoexpression of ERp in BPH was also higher than in normal prostates and localized only in the epithelium.8
In prostate cancer specimens, the expressions of both ERa and ERp have been studied for years,6,8,13,18 however, the relative expression levels and location of ERs in prostate cancer are still controversial. Using methods of immunohistochemistry staining, loss or down-regulation of ERa in prostate cancer has been reported.19,20 It appears ERa gene is transcriptionally inactivated by DNA methylation in most prostate cancer cells lines and specimens.11,21 Conversely, several groups reported the higher ERa expression in the prostate cancer specimens than in BPH and normal prostate tissue, which is consistent with other reports that abundance of ERa is positively correlated with the malignancy of prostate cancer.7,17
In terms of ERp expression, Royuela et al. (2001) reported the ERp has increasing epithelial staining in both BPH and prostate cancer, and some stromal cells acquire ERp in prostate cancer specimens, not in normal prostate and BPH. These findings suggest the involvement of ERp in prostate cancer. However, recent reports showed a frequent loss of ERp expression in prostate cancer samples relative to normal prostate tissue.13'18'22 In the primary prostate tumor sites, ERp was strongly expressed in low grade prostate carcinoma and was markedly diminished in higher grade tumor.18,22,23 These results suggested ERp may protect against abnormal prostate cell growth.11'13,22 Loss of ERp may cause prostate epithelial cells to escape the control of proliferation by ERp in prostate cancer. Further studies indiated ERp protein expression was significantly elevated in metastatic prostate tumor.13 Currently it is unclear why the ERp expression will be decreased in the higher grade prostate cancer and re-elevated in metastases. One hypothesis is that the failure to lose ERp may allow the cancer cells to gain the metastatic potential, and another could be the local environment in the distal metastatic sites may induce ERp expression. Although the controversy of ERs expression exists, the accumulating evidence shows the abnormality of ER signaling may contribute to the pathogenesis of prostate cancer.
The expression patterns of both ERs in different prostate cancer cell lines has been studied recently. The earlier studies on the effect of estrogens on prostate cancer cells growth showed the direct role of estrogen via their own receptors, but the specific ER has not been defined. Using RT-PCR, Lau et al. (1999) showed ERp, but not ERa, was found in normal prostate epithe-lia cells, along with pS2 and PR mRNA expression. Only ERp is detectable in LNCaP and DU145 cell lines, whereas PC-3 and BPH-1 expressed both ERa and ERp.11 Currently, there are two ERp isoforms, ERp1 and ERp2. Only ER£1 was detectable in PC-3, DU145, and LNCaP cell lines, whereas ERp2 was absent.24 Together, these studies suggested ERp could be the key player of estrogen-mediated effects in prostate cancer cell lines.
In rodents, it was found that ERa mRNA was the major type of ER expressed in two-week-old rat prostate and that as the rat aged ERp became the dominant expression.25 In agreement with the results from human prostate, it was found that ERa protein is predominantly located in the stroma cells of ventral prostate of adult rodents, with over 90% of the epithelial cells stained positive for ERp.26
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