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From the Institute of Pathology, University of the Saarland, Homburg/Saar, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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) in premalignant lesions and
prostatic adenocarcinoma through the various stages of the disease.
Conversely, the novel characterized ERß subtype was
undetectable in human prostate tissue. High-grade prostatic
intraepithelial neoplasia revealed ER mRNA and protein expression in
28% and 11% of cases evaluated. Focal ER immunoreactivity was
detected in a minority of low- to intermediate-grade adenocarcinoma.
High-grade (primary Gleason grade 4 and 5) tumors revealed ER protein
expression in 43% (62% respectively) of cases. The most significant
ER gene expression on mRNA and protein levels was observed in
hormone refractory tumors and metastatic lesions, including
lymph node and bone metastases. Results of the current study suggest
that estrogens can affect prostatic cancerogenesis and neoplastic
progression through an ER-mediated process in human prostate
tissue.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The role of estrogens in prostate cancer
progression is even less well understood. It is generally accepted that
estrogens influence prostatic growth indirectly through effects at the
hypothalamic and pituitary levels, reducing gonadotrophin secretion and
hence the synthesis of testicular testosterone.12
This
concept is supported by immunohistochemical and in situ
hybridization (ISH) studies that failed to demonstrate detectable
levels of the estrogen receptor (ER) in epithelial compartments of
human prostate cancer.13-19
Nevertheless, ER gene
expression has been reported in several human prostate cancer cell
lines, including LNCaP, PC-3, and DU-145,20,21
although
these data have not been confirmed by others.19
A recent
study using RT-PCR, ligand binding assays, and immunohistochemistry
(IHC) failed to demonstrate detectable ER in prostate cancer cell lines
and tissue sections from patients with metastatic
disease.19
Regardless of these divergent findings, the
recent discovery of an additional ER subtype has shed new light on the
role of estrogens in prostate tissue.22-24
The novel
ERß cloned from a rat prostate cDNA library is expressed at high
levels in epithelial compartments of the rat prostate
gland.22,25
Its presence in human prostate tissue and
prostatic adenocarcinoma, however, has not yet been reported in the
literature. The ERß shares high homology with the known ER protein
(consequently ER) in the DNA binding domain but differs in the
ligand and transactivation domains.22-24
In human
prostate tissue, the classical ER has been detected exclusively in
stromal compartments and in subsets of basal
cells.13,14,16,17
Thus it is generally believed that
ER-mediated effects on the prostatic epithelium are exerted via
paracrine mechanisms.
The controversial issue of the potential implications of estrogens in
neoplastic prostate growth prompted us to investigate ER gene
expression in human prostate tissue by combined immunohistochemical and
mRNA ISH techniques. Using improved antigen retrieval methods and the
well-characterized antibody NCL-ER-6F11 directed against the whole
protein of the classical ER,26
we were able to demonstrate
the nuclear ER in 11% of HGPIN and in a significant number of
high-grade, metastatic, and hormone-insensitive prostatic
adenocarcinomas. On the other hand, the ERß was undetectable in
prostate tissue by IHC. ER gene expression was confirmed by ISH
showing high steady-state levels of ER mRNA in premalignant and
malignant human tissue, even in the absence of detectable ER
protein.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Formalin-fixed, paraffin-embedded, and fresh frozen tissue
sections were obtained from 28 patients who underwent radical
prostatectomy and pelvic lymphadenectomy for prostate cancer during the
period from 1991 to 1998. The pathological stages included pT3c
(n = 14), pT3a,b (n = 9),
pT2 (n = 5), pN1 (n = 9)
(Table 1)
. Tissue sections from radical
prostatectomy specimens submitted for study contained the Gleason
primary grades 2 (n = 8), 3
(n = 25), 4 (n = 28), and
5 (n = 18). High-grade prostatic intraepithelial
neoplasia (HGPIN) was identified in all prostatectomy specimens. The
extend of HGPIN was arbitrarily defined by one microscopic field at low
magnification (x100). One hundred seventy-six foci of HGPIN were
submitted for study. The material further contained bone metastasis
from two patients without previous hormonal therapy and palliative
transurethral resection specimens from 18 patients with recurrent
prostatic adenocarcinoma after orchiectomy (Table 1)
. Antibody
specificity for the ER and ß subtypes was tested in ovarian tissue
obtained from five patients with cervical carcinomas. Paraffin-embedded
tissue sections were cut 1 day before pretreatment and staining.
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Tissue sections were deparaffinized, rehydrated through graded
alcohol, and subsequently incubated in H2O2
(0.3%) to block endogenous peroxidase. For microwave-based antigen
retrieval, sections were microwaved (750 W for 5 minutes and 450 W for
5 minutes) in 10 mmol/L citrate buffer (pH 6.0). After pretreatment,
the sections were incubated for 30 minutes in a normal rabbit serum
(Dako, Hamburg, Germany). The mouse monoclonal antibody NCL-ER-6F11,
directed against the full-length ER molecule (Novocastra Laboratories,
Newcastle upon Tyne, UK) was obtained by recombinant protein
preparation from MCF-7 cells.26
Specificity was tested by
Western blotting and by IHC on breast and other tissues.26
In comparative studies, NCL-ER-6F11 was recognized to be more effective
than other available ER antibodies.26
To localize the
ER, we have used the NCL-ER-6F11 antibody in a dilution of 1:200.
Sections were incubated overnight in a humid chamber. After incubation
with the secondary biotinylated rabbit anti-mouse immunglobulin (Dako)
for 30 minutes, the horseradish peroxidase-labeled avidin-biotin
complex (ABC-HRP) method (Dako) was performed according to the
manufacturer's instructions. A signal amplification method based on
the deposition of biotinylated tyramine was used to enhance
immunodetection of the ER. Preparation of the biotinylated tyramine
reagent was recently described in greater detail.27
After
precipitation of the biotinylated tyramine (10 minutes at room
temperature) through the enzymatic action of HRP and
H2O2 (0.1%), the biotin precipitate was
detected with an additional application of the HRP-labeled
avidin-biotin complex (Dako) for 30 minutes in a humid chamber. The
peroxidase reaction was developed by 3,3'-diaminobenzidine (Sigma,
Deisenhofen, Germany), leaving a brown end product. Negative controls
were performed on consecutive sections by replacing the primary
antibody with a nonimmune mouse serum.
To localize the ERß subtype, we have tested two commercially available antibodies in routinely processed and frozen tissue sections. The 65-kd anti-rat estrogen receptor ß (Upstate Biotechnology, Lake Placid, NY) and the 210–180-C050 antibody (Alexis Corporation, Nottingham, UK) were obtained by immunizing rabbits with synthetic peptides representing the N-terminal amino acids 46–63 and the C-terminal amino acid residues 467–485 of human ERß, respectively. The specificity of these antibodies was tested by Western blot analysis. For microwave-based antigen retrieval, the deparaffinized slides were microwaved in Target Retrieval Solution (pH 6.1) (Dako) for 30 minutes according to the manufacturer's instructions. Frozen sections did not require microwave pretreatment. After incubation of the slides with a normal swine serum (Dako), the ERß antibodies were applied in a dilution of 1:100 overnight. Detection was achieved as described above, except that the secondary biotinylated rabbit anti-mouse immunglobulin was replaced by the biotinylated swine anti-rabbit antibody (Dako).
In Situ Hybridization Analysis
Twenty-four base cDNA oligonucleotide antisense and sense probes
(antisense: 5'-CTC CAG CTC GTT CCC TTG GAT CTG-3'; sense: 5'-CAG ATC
CAA GGG AAC GAG CTG GAG-3') complementary to human ER mRNA coding
for amino acids 17–24 were synthesized from MWG-Biotech (Ebersberg,
Germany). This antisense probe sequence is located within a 72-base
region of ER mRNA that shows no homology with glucocorticoid,
mineralocorticoid, or progesterone receptors.28,29
Using the BLAST sequence similarity search tool provided by the National Center for Biotechnology Information (Bethesda, MD), the published ERß cDNA sequences30,31 revealed no homology of the oligonucleotide probe used for the mRNA-ISH assay.
The oligonucleotides (antisense probe and sense probe for negative control) were biotin-16-2'-desoxyuridine-5-triphosphate (bio-16-dUTP) (Boehringer Mannheim, Mannheim, Germany) 3'-tailed with the DNA tailing kit (Boehringer Mannheim). The labeling procedure was performed according to the manufacturer's instructions (Boehringer Mannheim). The efficiency of labeling reaction was checked on dot blot dilution series.
A standard nonradioactive in situ hybridization method was used as described elsewhere,32 with slide modifications. In brief, 5-µm sections were deparaffinized in xylene (2 x 15 minutes) (Merck, Darmstadt, Germany), rehydrated through graded alcohol, and pretreated with 10 µg/ml proteinase K (30 minutes, 37°C) (Boehringer Mannheim). After they were washed twice in 2x standard saline citrate (20x SSC stock solution: 3 mol/L NaCl, 0.3 mol/L sodium citrate, pH 7.0) (Merck), the slides were covered with 40 µl of the prehybridization buffer containing 2x SSC, 1x Denhardt's solution (50x Denhardt's stock solution: 1% polyvinylchloride, 1% pyrrolidone, 2% bovine serum albumine) (Oncor, Heidelberg, Germany), 10% dextran sulfate (Boehringer Mannheim), 50 mmol/L phosphate buffer (pH 7.0) (Merck), 50 mmol/L 1,4-dithiothreitol (DTT) (Boehringer Mannheim), 250 µg/ml yeast tRNA (Boehringer Mannheim), 100 µg/ml polyadenylic acid (Boehringer Mannheim), 500 µg/ml denatured and sheared DNA from fish sperm (Boehringer Mannheim), and 26.7% deionized formamide (Oncor) and incubated for 2 hours at 37°C in a humid chamber. The sections were hybridized overnight at 37°C with 40 µl hybridization mixture containing the hybridization buffer and 10 pmol/L labeled oligonucleotide probe per slide.
After the slides were washed in graded concentrations of SSC (2x, 1x, 0.25x); slides were washed twice in each concentration for 30 minutes in a shaking water bath at 37°C). Detection was achieved by the ABC method with the tyramine amplification method described above, leaving a brown end product. The slides were counterstained with hematoxylin.
To prove the specificity of the hybridization process, the following negative controls were performed in each case. The slides were hybridized with the corresponding sense probe. The hybridization procedure was then performed by omitting the sense and antisense probes. In addition, slides pretreated with RNase (Boehringer Mannheim) were hybridized as described above.
Quantitative Analysis of Staining
The staining results obtained by IHC and ISH analysis were classified into six categories ranging from 0 to 5: 0: no staining detectable; 1: less than 5% positive tumor cells; 2: 5–25% positive tumor cells; 3: 25–50% positive tumor cells; 4: 50–75% positive tumor cells; 5: more than 75% positive tumor cells.
Differences in staining intensities obtained by IHC or ISH results were not considered in the scoring system.
HGPIN was evaluated by reporting the presence or absence of detectable
ER protein and mRNA expression in each lesion defined by one
microscopic field at low magnification (x100).
Statistical Analysis
Contingence table and 
2
analyses were used to study
the relation between the ER-IHC score and the primary Gleason grade of
primary adenocarcinomas, recurrent disease, and metastases. Statistical
analyses were performed with SPSS software (SPSS ASC GmbH, Erkrath,
Germany). P < 0.05 was regarded as statistically
significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and ERß in Benign Ovarian and
Prostate Tissue
Among the three antibodies tested in the current study, only the
NCL-ER-6F11 antibody directed against the classical ER yielded distinct
nuclear immunolocalization in benign and malignant prostate tissue.
Using the polyclonal 210-180-C050 and the 65-kd anti-rat ERß
antibody, we were unable to demonstrate any reliable nuclear staining
in both routinely processed and frozen sections of prostate tissue. On
the other hand, distinct nuclear ERß positivities were identified in
granulosa and theca cells, which served as positive controls (Figure 1a)
. To test the specificity of the
NCL-ER-6F11 antibody for ER, immunohistochemical and ISH analyses
were performed in ovarian tissue expressing ERß. We failed to
demonstrate immunoreactive granulosa and theca cells, although these
cells revealed detectable levels of ER mRNA. In benign prostate
tissue, ER mRNA and protein expression was restricted to stromal and
basal cells (Figure 1b)
but was undetectable in secretory luminal cells
reported for the presence of the ERß at high levels in rat
tissue.22,24,25
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Expression in HGPIN and Prostate Cancer
Using the NCL-ER-6F11 antibody and the staining protocol described
above, we were able to demonstrate ER gene expression in both
stromal and epithelial compartments of HGPIN and prostatic
adenocarcinoma (Figures 2–4)
.
The IHC and ISH results obtained in epithelial compartments are
summarized in Tables 2 and 3
. ER protein expression was found in
11% of 176 HGPIN lesions evaluated (Figure 2a)
. Forty-seven of 168
cases of HGPIN submitted for ISH analysis (28%) revealed detectable
mRNA transcripts in the dysplastic epithelium (Figure 2b)
. Low- to
intermediate-grade prostatic adenocarcinoma (primary Gleason grades 2
and 3) showed focal ER positivities in up to 20% of cases (Table 2)
.
Gleason grade 4 and 5 carcinomas variably expressed the ER protein in
43% (respectively 61%) of cases (Figure 4a)
. Five Gleason grade 4 and
three Gleason grade 5 tumors were identified with significant staining
(>25% immunoreactive tumor cells). Statistical analysis showed a
significant positive correlation between the ER-IHC score and the
primary Gleason grade (P < 0.001). Recurrent
adenocarcinoma after hormonal therapy expressed the nuclear ER in 94%
of cases (Table 2)
. Significant staining (>25% immunoreactive tumor
cells) was recorded in 10 of 18 cases (55.5%) of recurrent
adenocarcinoma. Eight lymph node metastases and two bone metastases
were ER positive (Figure 4b)
. Significant staining (>25% positive
tumor cells) was noted in five of 11 cases (45.5%) of metastatic
lesions. Statistical analyses comparing high-grade (primary Gleason
grades 4 and 5) adenocarcinoma with recurrent and metastatic tumors
showed a significant positive correlation with the ER status
(P < 0.001).
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mRNA. Table 3
summarizes the ISH results
obtained in specimens lacking the ER protein in epithelial
compartments. A significant number of ER-negative lesions (71.5% of 49
cases) revealed detectable steady-state levels of ER mRNA (Figure 3)
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) and has a wide application in routine
practice in the assessment of the ER status in breast and endometrial
neoplasias.26
There is currently no convincing evidence
that this antibody cross-reacts with ERß. For example, granulosa and
theca cells expressing ERß were unreactive with NCL-ER-6F11.
Furthermore, the differential expression of ER mRNA and protein
obtained in human prostate tissue differed significantly from the
immunolocalization of ERß reported in the rat prostate
gland.22,24,25
HGPIN is considered to be the most likely precursor of intermediate-
and high-grade prostatic adenocarcinoma.33,34
In our
series, approximately 11% of these precursor lesions expressed the
classical ER in the dysplastic epithelium. In addition, ISH analysis
revealed ER transcripts in 28% of HGPIN investigated. No
correlation was found between the ER status in HGPIN and that of
invasive cancer present in the same tissue section. The presence of
ER clearly indicates that subsets of HGPIN are estrogen-responsive
through a receptor-mediated process. Interestingly, a recent study has
identified the estrogen-inducible PS-2 protein in a significant number
of nonneoplastic and dysplastic prostate tissue from patients with
locally advanced prostate cancer, but not in prostate tissue from
patients without evidence of malignant disease.35
These
data, along with evidence from experimental and epidemiological
studies,1-11
suggest that estrogens can affect early
phases of prostatic carcinogenesis through an ER-mediated pathway. This
warrants further investigations of surrogate markers of estrogen action
and estrogen-regulated genes to define their role in the malignant
transformation of the prostatic epithelium.
Results of the current study clearly demonstrate the presence of the
nuclear ER in stromal and epithelial compartments of common prostatic
adenocarcinoma. In primary tumors, the extent of detectable ER in
epithelial compartments correlated significantly with the primary
Gleason grade. Low- to intermediate-grade adenocarcinoma expressed the
ER protein in a minority of cases. On the other hand, high-grade
(primary Gleason grades 4 and 5) tumors revealed at least focal ER
positivities in 43% (respectively 61%) of cases. The most
consistent and extensive ER mRNA and protein expression observed in
the current study was detected in recurring carcinomas after hormonal
therapy and in metastatic lesions, including lymph node and bone
metastases. In particular, hormone refractory and metastatic lesions
showed significant ER protein expression (>25% immunoreactive tumor
cells) in 55.5% and 45.5% of cases evaluated. It is noteworthy that
the levels of ER detected by ISH were significantly higher than that
obtained by IHC. These apparent discrepancies in ER protein and mRNA
expression are difficult to interpret. It is possible that receptor
saturation by ligand binding and subsequent degradation of the
ER-ligand complex accounts for decreased detection of the ER protein by
IHC. Whether more powerful IHC techniques can increase the detection
rate of nuclear ER in prostatic adenocarcinoma remains to be
established.
In summary, the preliminary data presented here suggest that the progressive emergence of the classical ER in common prostatic malignancies runs parallel to the process of dedifferentiation, metastasis, and androgen insensitivity. This observation may have clinical implications, inasmuch as androgen ablation therapy increases the estrogen/androgen ratio in cancerous tissue. Tumor cells expressing the ER protein are potentially estrogen-responsive and may survive in an androgen-deprived milieu by using estrogens for their continuous maintenance and growth. Much more work is needed to define the molecular bases of ER gene expression and its downstream effector pathways during prostatic carcinogenesis and progression to androgen-insensitive disease. Progress in this field may lead to novel therapeutic strategies interfering with the ER-mediated process. The occurrence of the classical ER in a substantial number of androgen-insensitive and metastatic carcinomas raises the question of whether these tumors should be treated with antiestrogens when the ER protein is detectable in cancerous tissue.
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Footnotes |
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Supported by Deutsche Forschungsgemeinschaft grant Bo 1018/2-2.
Accepted for publication April 28, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and ß. Endocrinology 1997, 138:863-870 in vivo and in vitro. Biochem Biophys Res Commun 1998, 243:122-126[Medline]
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