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Cancer Research Program, Garvan Institute of Medical Research, [L. G. H., S. M. H., D. R. H., D. I. Q., R. L. S.], and Departments of Urology [D. G., P. C. B., G. O., R. K., P. D. S.] and Medical Oncology [J. J. G.], St. Vincent’s Hospital, Darlinghurst, Sydney, NSW 2010, Australia; Department of Anatomical Pathology, Royal Prince Alfred Hospital and Department of Pathology, University of Sydney, Camperdown, NSW 2050, Australia [C. S. L.]; Department of Medical Nutrition and Biosciences, Karolinska Institute, NOVUM, S-141 86 Huddinge, Sweden [S. M., J-A. G.]; and Douglass Hanly Moir Pathology, North Ryde, NSW 2113, Australia [W. D.]
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ABSTRACT |
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is expressed only in the stroma, whereas estrogen receptor-ß (ERß) is present in both normal stroma and epithelium. Because loss of ERß expression is associated with prostate hyperplasia in ERß-null mice, this study determined patterns of ERß expression in normal, hyperplastic, and malignant human prostate and associations with clinical outcome. Five normal prostates from organ donors and 159 radical prostatectomy specimens from patients with clinically localized PC were assessed for ERß expression using immunohistochemistry. ERß-positivity was defined as 
5% of cells demonstrating nuclear immunoreactivity. All of the five normal prostates showed strong ERß-nuclear staining in >95% of the epithelium and 35% of the stromal cells. The number of ERß-positive cases declined to 24.2% (38/157) in hyperplasia adjacent to carcinoma and 11.3% (18/159) in PCs. ERß-positivity was related to decreased relapse-free survival (log-rank P = 0.04). Thus, loss of ERß expression is associated with progression from normal prostate epithelium to PC, whereas those cancers that retained ERß expression were associated with a higher rate of recurrence. These data identify the need to further investigate the potential role of ERß in the regulation of prostate epithelial cell proliferation and the functional consequences of decreased ERß expression in the evolution of PC. |
Introduction |
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Interest in the role of ERs in human PC was further stimulated by the cloning and characterization of a second ER, ERß (3)
. The classical ER, ER, is present in normal and malignant prostate stroma but not in the epithelium (4)
. Thus, it was assumed that estrogen action on prostate tissue was mediated through modulation of androgen receptor signal transduction or other paracrine mechanisms. In contrast, ERß is highly expressed in rat prostate epithelial cells and in the secretory epithelium of normal human prostate, where the levels of ERß mRNA are higher than the levels of ER mRNA (3)
. These data and the observation that older ERß-null mice develop prostatic hyperplasia (5)
have led to the hypothesis that loss of ERß may be a mechanism by which prostate epithelial cells escape normal control of proliferation (6)
. Hence, the aim of this study was to define the pattern of ERß protein expression in normal and malignant human prostate tissue and to determine whether changes in expression were associated with disease progression and prognosis.
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Materials and Methods |
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Patients were followed postoperatively by their surgeons on a monthly basis until satisfactory urinary continence was obtained and then at 3-month intervals until the end of the first year, six-month intervals to 5 years, and yearly thereafter. Relapse was defined by biochemical disease progression with a serum PSA concentration 0.4 ng/ml rising over a 3-month period or by local recurrence on digital rectal examination confirmed by biopsy or by subsequent rise in PSA.
Pathological assessment of the RP specimens revealed 35% (55/159) had organ-confined tumors, 20% (32/159) had seminal vesicle involvement, 2% (3/159) had pelvic lymph node metastases, and 52% (83/159) had surgical margins involved with tumor. The mean Gleason score at RP was 7 (range, 4–10) whereas the median preoperative PSA was 10.7 ng/ml (n = 156; range, 1.9–182.0 ng/ml). At a median follow-up of 64.7 months (range, 1–135), 47/159 (29.6%) patients had relapsed. The median time to relapse was 21.0 months (range, 0.2–80.7). Five patients (3.2%) died of PC during the study period. Univariate and multivariate analyses were performed to demonstrate that the cohort as a whole was similar to other RP cohorts reported in the literature (7 , 8) .
As there is essentially no normal tissue associated with PC because all of the epithelial cells are included in the field change that accompanies cancer, normal human prostate tissue was obtained from five men at the time of organ donation for transplantation. The mean age of these men was 25.6 years (range, 17–33 years). No other information was available on these subjects. All of the normal prostate tissue used was from the peripheral zone, because this is the area from which most PCs arise.
Immunohistochemistry.
Paraffin blocks of formalin-fixed surgical specimens were obtained from the archives of the Department of Anatomical Pathology at St. Vincent’s Hospital, Sugerman Hampson Macquarie Pathology (Sydney, Australia) and Douglass Hanly Moir Pathology (Sydney, Australia). Pathological evaluation of all of the blocks from each prostate was performed by one of three histopathologists. Tumor stage was classified according to the Tumor-Node-Metastasis staging system and Gleason grade. Up to 3 blocks of each case were sectioned and stained with H&E. A block most representative of each cancer was selected for assessment. Normal prostate tissue was frozen at collection and subsequently formalin-fixed and paraffin-embedded. Serial 5-µm sections were mounted on Superfrost Plus adhesion slides (Lomb Scientific, Australia). All of the cancer and normal prostate cases were analyzed for ERß expression by IHC.3
Serial sections were used to stain 40 PC cases and the normal prostate cases for ER expression to demonstrate differential staining for ER and ERß. The normal prostate cases were also stained for high molecular weight cytokeratin and PSA to define the basal and secretory epithelial compartments, respectively (9)
.
ERß was detected using a chicken polyclonal antibody (ERß 503 IgY3) developed at the Karolinska Institute against recombinant human ERß protein. The characterization of this antibody has been reported previously (6
, 10
, 11)
. As a positive tissue control, a specimen of normal breast, which has high levels of ERß expression (3)
, was included (Fig. 1A)
. In addition, paraffin-embedded cell pellets of breast cancer cell lines of known ERß status, MCF-7 and ZR-75–1, were used as positive and negative tissue controls, respectively (3)
, whereas the same cell pellet of MCF-7 cells incubated in diluent without antibody was the negative technical control. The sections were dewaxed and rehydrated before unmasking in target retrieval solution (pH 6.0; DAKO, Carpinteria, CA). The sections were initially incubated for 30 min with 1:750 ERß 503 antibody and, subsequently, for 15 min with 1:200 biotinylated goat antichicken antibody (Vector Laboratories, Burlingame, CA). A streptavidin-biotin peroxidase detection system was used according to the manufacturer’s instructions (Vectastain Elite kit; Vector Laboratories) with 3,3'-diaminobenzidine as substrate. Counterstaining was performed with Whitlock’s hematoxylin (BDH Laboratory Supplies, Poole, United Kingdom). The same protocol was used to detect ER except for the use of a mouse antihuman ER monoclonal antibody 1:50 (Clone 1D5; DAKO). As a positive ER control, a breast cancer specimen with high levels of ER was included. In addition, paraffin-embedded cell pellets of a PC (LNCaP) and breast cancer (MCF-7) cell line were used as negative and positive controls, respectively, whereas the same cell pellet of MCF-7 cells incubated in diluent without antibody was the negative technical control.
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ISH.
ISH was performed on normal human breast tissue (Fig. 1B)
, MCF-7 cells, ZR-75–1 cells, and normal prostate tissue to confirm antibody specificity by colocalization of ERß mRNA and protein in contiguous sections of tissue and cell lines of known ERß status. A 425-bp probe for ERß was derived by PCR from the 3' end of the ERß cDNA (nucleotides 1136–1560). This was transcribed to produce a DIG3
-labeled riboprobe using an RNA DIG-labeling kit (Roche, Mannheim, Germany).
The tissue was processed as described previously, and 3-µm sections were cut, dewaxed, rehydrated through graded ethanol, and treated with 0.2 M of HCl before unmasking with 0.5 µg/ml proteinase K (Roche) for 30 min at 37°C. An acetylation step was performed before prehybridization at 55°C for 2 h using a hybridization solution containing 4 µg/ml sheared salmon sperm DNA (Roche), 4 µg/ml tRNA (Roche), and 10 µg/ml yeast total RNA (Roche). Sections were hybridized overnight at 55°C with the hybridization solution described previously and 250 ng/ml-labeled ERß riboprobe.
Decreasing concentrations of SSC (2x, 1x, and 0.5x) were used as stringency washes followed by RNase digestion of the unhybridized probe. Detection was achieved using anti-DIG-antibody-AP (Roche) and nitroblue tetrazolium/5-bromo-4-chloro-3-indolyl phosphate (Roche).
Assessment of Immunohistochemistry.
Immunostaining was initially assessed by one investigator (L. H.) and subsequently reviewed independently by a histopathologist (C. S. L.). Both individuals were blinded to patient outcome. Significant cytoplasmic staining has been noted by others using immunohistochemical assessment of ERß expression, although its relevance is not known (12)
. We also found significant cytoplasmic staining in the presence and absence of nuclear staining. Given previous evidence that ERß is a nuclear-localized steroid receptor, only positive nuclear immunostaining was scored. Counting of 200 cancer cells in each tumor was undertaken to determine the percentage of immunostained nuclei across all of the areas of cancer present. This procedure was repeated for areas of hyperplasia and for the stroma. The interobserver Spearman rank coefficients for ERß scores were between 0.72 and 0.79, signifying close agreement between observers. All of the discrepancies in scoring were reviewed and a consensus reached. Two levels of expression were considered for the cutoff of ERß positivity, 1% and 5% of cells demonstrating nuclear immunoreactivity. The primary analysis was based on a cutoff of 5%. Sections stained for ER were similarly scored by counting cells with nuclear immunoreactivity and classified as positive if 5% of cell nuclei were immunoreactive.
Statistical Analysis.
The results were reported as proportions within histological groups. Disease-specific relapse was measured from the date of RP to the date of last follow-up. Data were evaluated for disease relapse using the method of Kaplan-Meier and log-rank test and by univariate and multivariate analyses in a Cox proportional hazards model for ERß status and other clinical and pathological predictors of outcome. The multivariate model was produced by assessing ERß status with other baseline covariates of clinical relevance such as Gleason grade, pathological stage, and preoperative PSA, which were modeled as dichotomous or continuous variables as appropriate. The associations between ERß expression and discrete categorical variables were tested using the 
2 test. A P of <0.05 was required for significance. All of the reported Ps are two-sided. All of the statistical analyses were performed using Statview 4.5 software (Abacus Systems, Berkeley, CA).
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Results |
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Expression in PC., but 16 had stromal staining of 5% positive nuclei. This did not correlate (2 test) with ERß-positivity in the cancer (P = 0.17), hyperplasia adjacent to carcinoma (P = 0.45), or the stroma (P = 0.07). Only 5 cases coexpressed ERß and ER in the stroma.
ERß Expression in Normal Prostate Tissue.
All of the five normal prostate specimens had >95% ERß immunoreactivity in the ductal epithelial nuclei. Detection of high molecular weight cytokeratin and PSA immunoreactivity delineated the basal and secretory epithelial cell compartments of the normal epithelium, respectively, such that a comparative analysis of the immunohistochemistry revealed that ERß protein was expressed in both the basal and secretory cells of the epithelium (Fig. 1, C–F)
. In addition, detection of ERß mRNA using ISH confirmed colocalization of ERß mRNA and protein in both compartments of the epithelium (Fig. 1G)
. The stroma was also positive in all of the cases with 20–60% of stromal nuclei immunoreactive. In contrast, ER was not present in the epithelium, but 10–20% of the stromal cells in all of the five specimens expressed ER.
ERß Expression in Prostatic Hyperplasia.
Of the 157 sections containing hyperplasia adjacent to carcinoma, 38 had 5% ERß-positive cells in the epithelium (see Fig. 1H
). The distribution of scores is presented in Table 1
. Of the 38 ERß-positive cases of hyperplasia, 23 had ERß expression (5% of cells) in the adjacent stroma, and 11 were adjacent to ERß-positive cancers. There was no differential pattern of ERß expression between those cases in which the hyperplasia alone was ERß-positive and those in which the adjacent cancer was also ERß-positive. There was no relationship between ERß positivity in hyperplasia adjacent to carcinoma and relapse-free survival (P = 0.52).
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5% ERß-positive cells in 34 of the 159 cases. The distribution of the immunoreactive cells was similar for stroma surrounding malignant and benign areas. The presence of ERß expression in the stroma did not predict outcome (P = 0.72).
ERß Expression in PC.
Of the 159 cancer specimens, only 18 were ERß-positive at a cutoff of 5% positive nuclei (see Fig. 1I
). The distribution of scores is presented in Table 1
. There was no difference between the ERß-positive group and the RP cohort as a whole in regard to clinicopathological parameters apart from a higher rate of perineural invasion (78% versus 56%). In 8 of the ERß-positive cases, the cancer invading the nerves contained ERß-positive cells on the sections examined.
Nine of the 18 (50%) ERß-positive cases had relapsed at a median follow-up of 6 years. Two had local recurrences associated with an increased PSA, whereas 7 had an increase in PSA alone. All were hormone-sensitive at last follow-up. Patients whose cancer was ERß-positive had a significantly decreased relapse-free survival as determined by Kaplan-Meier analysis (see Fig. 2A
) compared with those who were ERß-negative (P = 0.04).
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5% of cells, both observers consistently noted scores below this threshold (Table 1)
. The significant decrease in disease-free survival for ERß-positive cases was robust at all of the cutoffs between 1% and 5%. At a cutoff of 1%, 37/159 (23%) of the cohort had ERß-positive cancers. Half of these patients had relapsed at a median follow-up of 6 years, and Kaplan-Meier analysis (Fig. 2B)
demonstrated decreased disease-free survival in the ERß-positive group (P = 0.002). Of interest, when ERß expression at a cutoff of 1% was modeled in a multivariate analysis with pathological stage (P = 0.006), RP Gleason score (P = 0.02), involved surgical margins (P = 0.85), and preoperative PSA (P = 0.14), it was an independent predictor of prognosis (P = 0.04). |
Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Whereas ERß mRNA and protein have been detected in the epithelial and stromal cells of normal human prostate (12, 13, 14) , there have been no consistent findings in regard to ERß and PC. A recent study demonstrated a decrease in ERß mRNA expression in a majority of clinically localized and hormone-refractory prostate tumors relative to normal tissue (14) . Interestingly, a few cases in each group showed no change or increased ERß expression in the tumor compared with normal tissue (14) . Bonkhoff et al. (15) were unable to detect ERß expression in 28 primary PCs by IHC. The low rate of 11.3% ERß positivity in our cohort may explain why this group was unable to demonstrate ERß expression in their much smaller cohort. An alternative explanation may relate to different sensitivities of the antibodies used in the two studies.
Studies of breast and colon cancers demonstrate similar patterns of loss of ERß expression with development of carcinoma. ERß mRNA and protein have been detected in normal breast epithelium, but there was a trend toward loss of mRNA expression in adjacent cancers (3 , 12 , 16) . Similarly, selective loss of ERß protein in colon cancers compared with matched normal tissue has been demonstrated (17) . Therefore, the present study represents the first published research on a large cohort of human cancers that establishes a relationship between loss of ERß expression and carcinogenesis.
Although ERß and ER have similar ligand-binding domains and both bind estrogen response elements, there is evidence that ERß and ER demonstrate distinct and sometimes opposing transcriptional activities (18
, 19)
. Paech et al. (18)
demonstrated that 17ß-estradiol inhibited transcription via ERß but activated transcription when signaling through ER. Additionally, studies in cell culture found that ERß inhibited ER transcriptional activity at subsaturating levels of estradiol and decreased overall sensitivity of the cells to estrogen (19)
. A differential response to estradiol was also observed in the immature uterus of ERß knockout (BERKO) mice, which exhibited an enhanced response to estradiol compared with wild-type, ERß-positive mice. If transcriptional activity reflects the mitogenic effect of ERs, these studies and the finding that older ERß-null mice develop prostatic hyperplasia (5)
suggest that ERß is predominantly antiproliferative. The corollary of this is that loss of ERß, in conjunction with other unknown molecular events, may promote cell proliferation and possibly carcinogenesis. Such a hypothesis is compatible with the loss of ERß expression in prostatic hyperplasia and carcinoma observed in this study. Whereas the mechanism of this putative antiproliferative effect of ERß in human prostate is unclear, studies in BERKO mice also show that androgen receptor levels are elevated in the prostates of mice in which the ERß gene is inactivated (6)
. Because we have shown that ERß and ER are rarely coexpressed in the same cells of the human prostate, one possible mechanism is that down-regulation of androgen receptor levels by ERß results in limited epithelial cell proliferation.
Interestingly, the small group of prostate tumors that retained ERß expression had a poorer prognosis in regard to relapse. Although we acknowledge that there are caveats to these data because of the small number of patients that were ERß-positive, this result was robust at a number of cutoffs between 1 and 5%. There were no obvious differences in the clinicopathological parameters of the ERß-positive and -negative groups, suggesting the differences in outcome may relate directly to ERß expression. The inverse association between ERß positivity and Gleason score demonstrated for the 18 ERß-positive cancers in this study (data not shown) may be interpreted as evidence that ERß expression is independent of conventional clinicopathological characteristics such as grade. This finding is not explained by the current understanding of ERß function but may be accounted for by (1) the ERß expressed in PC being a variant of the wild type as has been described in breast cancer (20 , 21) , or (2) the wild-type ERß conferring a more aggressive phenotype in these cancers through alternative functions to those currently described in the literature. Given the long natural history of PC, longer follow-up will better test the association between ERß positivity and outcome.
In addition, expression of ERß mRNA in breast tumors has been associated with clinicopathological markers of poor prognosis. ERß mRNA expression in breast cancer biopsies correlated inversely with progesterone-receptor expression (22) . In addition, higher rates of ERß mRNA expression have been demonstrated in node-positive breast cancers compared with node-negative (16) and in tamoxifen-insensitive breast cancers compared with tamoxifen-sensitive tumors (23) . These relationships suggest that breast cancers that express ERß are likely to have a poorer prognosis, but this has yet to be proven.
Although antiestrogens have had little success in the past as a therapy for PC (24) , our results may identify a group of ERß-positive PC patients in which these agents may have therapeutic benefit. Recently published data have shown that the antiestrogens ICI 182,780 and tamoxifen inhibit the growth of androgen-independent PC cell lines PC-3 and DU-145 (13) . Furthermore, unlike PC-3 cells, DU-145 cells express ERß exclusively and can be rescued from ICI 182,780 growth inhibition by treatment with ERß-antisense oligonucleotides (13) . These data imply that ERß is involved in regulating the proliferation of androgen-insensitive PC cells. These findings, in conjunction with data on the negative transcriptional effect of antiestrogens regulated through ERß (18 , 19) , suggest these drugs may be useful in a small group of PC patients whose tumors express ERß.
The loss of ERß in the majority of PCs is consistent with a role for ERß as a potential tumor suppressor gene; however, the finding that ERß expression in a small number of PCs confers a poorer prognosis implies a more complex function. More mature follow-up of the cohort may better elucidate this association. Additional studies are needed to address the role of ERß in the regulation of prostate epithelial cell proliferation at different stages in the development of PC. A better understanding of the function of ERß in the evolution of PC could potentially impact on the therapeutic options for patients who have ERß-expressing tumors.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by grants from the National Health and Medical Research Council of Australia (NHMRC), the New South Wales Cancer Council, the Freedman Foundation, the R. T. Hall Trust, the Ronald Geoffrey Arnott Foundation, the David Wilson Trust, and the St. Vincent’s Clinic Foundation. Lisa Horvath is the recipient of an NHMRC Medical Postgraduate Research Scholarship. 
2 To whom requests for reprints should be addressed, at Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia. Phone: 612 9295 8322; Fax: 612 9295 8321; E-mail: r.sutherland{at}garvan.unsw.edu.au
3 The abbreviations used are: PC, prostate cancer; PSA, prostate-specific antigen; ER, estrogen receptor; RP, radical prostatectomy; ISH, in-situ hybridization; IHC, immunohistochemistry; DIG, digoxigenin; Ig, immunoglobulin.
Received 2/15/01. Accepted 5/25/01.
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R. A. Jarred, M. Keikha, C. Dowling, S. J. McPherson, A. M. Clare, A. J. Husband, J. S. Pedersen, M. Frydenberg, and G. P. Risbridger Induction of Apoptosis in Low to Moderate-Grade Human Prostate Carcinoma by Red Clover-derived Dietary Isoflavones Cancer Epidemiol. Biomarkers Prev., December 1, 2002; 11(12): 1689 - 1696. [Abstract] [Full Text] [PDF]
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Z. Weihua, R. Lathe, M. Warner, and J.-A. Gustafsson An endocrine pathway in the prostate, ERbeta , AR, 5alpha -androstane-3beta ,17beta -diol, and CYP7B1, regulates prostate growth PNAS, October 15, 2002; 99(21): 13589 - 13594. [Abstract] [Full Text] [PDF]
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 M.-M. Liu, C. Albanese, C. M. Anderson, K. Hilty, P. Webb, R. M. Uht, R. H. Price Jr., R. G. Pestell, and P. J. Kushner Opposing Action of Estrogen Receptors alpha and beta on Cyclin D1 Gene Expression J. Biol. Chem., June 28, 2002; 277(27): 24353 - 24360. [Abstract] [Full Text] [PDF]
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V Speirs, G P Skliris, S E Burdall, and P J Carder Distinct expression patterns of ER{alpha} and ER{beta} in normal human mammary gland J. Clin. Pathol., May 1, 2002; 55(5): 371 - 374. [Abstract] [Full Text] [PDF]
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E. Corey, J. E. Quinn, M. J. Emond, K. R. Buhler, L. G. Brown, and R. L. Vessella Inhibition of Androgen-independent Growth of Prostate Cancer Xenografts by 17{beta}-Estradiol Clin. Cancer Res., April 1, 2002; 8(4): 1003 - 1007. [Abstract] [Full Text] [PDF]
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 E. Holter, N. Kotaja, S. Makela, L. Strauss, S. Kietz, O. A. Janne, J.-A. Gustafsson, J. J. Palvimo, and E. Treuter Inhibition of Androgen Receptor (AR) Function by the Reproductive Orphan Nuclear Receptor DAX-1 Mol. Endocrinol., March 1, 2002; 16(3): 515 - 528. [Abstract] [Full Text] [PDF]
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 C. A. Lamartiniere, J. Wang, M. Smith-Johnson, and I.-E. Eltoum Daidzein: Bioavailability, Potential for Reproductive Toxicity, and Breast Cancer Chemoprevention in Female Rats Toxicol. Sci., February 1, 2002; 65(2): 228 - 238. [Abstract] [Full Text] [PDF]
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