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Tumor Biology |
Westmead Institute for Cancer Research, University of Sydney at the Westmead Millenium Institute, [R. L. A-M., A. deF., P. A. M., C. L. C.], and Departments of Gynaecological Oncology [A. deF., G. V. W.], Tissue Pathology [R. C. J.], and Medicine [K. B.], Westmead Hospital, Westmead, New South Wales 2145, Australia
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSDISCUSSIONREFERENCES |
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Expression of high levels of PR3 is associated with better disease-free, and overall, survival and is an independent predictor of endometrial carcinoma outcome (9) . PR is encoded by a single gene encoding two proteins (10) , termed PRB and PRA, which are structurally different in that PRA is a truncated form of PRB, lacking 164 amino acids at the NH2 terminus. There is increasing evidence that, although both of the proteins bind progesterone, they have different capacities to activate target genes (11, 12, 13, 14, 15, 16, 17) . In cell culture, PRA and PRB have different abilities to activate transcription, with PRB being the more effective activator (14, 15, 16) , and PRA has a dominant negative effect on PRB and on glucocorticoid, androgen, and mineralocorticoid receptors in different mammalian cell lines (14 , 15 , 18) . Wen et al. (17) demonstrated, moreover, that PRA repressed estrogen receptor transcriptional activation. Taken together, evidence to date suggests that the PR isoforms have different functions on the activation of progestin-regulated promoters, and these differences change, depending on the target cell and gene promoter.
Because PRA and PRB have differing functions and because it has been shown that PRA and PRB exist at different relative levels in different tissues (19, 20, 21, 22, 23, 24) , differing ratios of PRA:PRB are likely to affect tissue responsiveness to progesterone. Because PR is an important indicator of response in endometrial cancer patients, but not all PR-positive patients respond, differential expression of PRA and PRB may be related to patient outcome and response to hormone therapy. The relative expression of PRA and PRB in endometrial cancers and their involvement in the pathogenesis of endometrial cancer is not known. The aims of this study were, firstly, to compare the ratio of PRA:PRB in tumors with adjacent normal endometrial glands and with adjacent endometrial hyperplasia, a precursor lesion of endometrioid adenocarcinoma; and, secondly, to determine the ratio of PRA:PRB expression in a cohort of endometrioid adenocarcinoma of the endometrium and correlate this with clinical features including surgical stage, FIGO grade, and nuclear grade.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSDISCUSSIONREFERENCES |
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is a summary of the clinical information on cases examined. Patients whose tumors contained more that 10% of another histological subtype of endometrial carcinoma were excluded from the cohort because different histological subtypes have different PR expression patterns (25
, 26)
. All archival, formalin-fixed, and paraffin-embedded tissues were acquired from the Department of Tissue Pathology at Westmead Hospital. A representative H&E-stained section of each tumor was regraded by a single pathologist (R. C. J.) according to FIGO grade and nuclear grade, to ensure that tumor grading was consistent across the study. Areas of hyperplasia were also identified and classified according to WHO classification. Control tissues, normal colon and normal myometrium, formalin-fixed and paraffin-embedded, were also obtained from the Department of Tissue Pathology, Westmead Hospital.
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Dual Immunofluorescent Staining.
Sections were stained for PRB and then for PRA as described previously (24)
. Briefly, to detect PRB, sections were incubated with a mouse antihuman PR monoclonal antibody that detects PRB only (hPRa6; Ref. 28
) and with a biotinylated goat antimouse antibody (Dako, Sydney, NSW, Australia), and TXR-avidin (Vector Laboratories, Burlingame, CA). To reveal PRA, sections were incubated with a mouse monoclonal antibody to detect PRA (hPRa7; Ref. 24
) and with a biotinylated goat antimouse antibody (Dako) and FITC-avidin (Calbiochem, Sydney, Australia). Sections were mounted with Vectashield mountant for fluorescence (Vector Laboratories) and stored in the dark at 4°C.
Under dual fluorescent excitation, PRB proteins that were labeled with TXR appeared orange; PRA proteins, labeled with FITC, appeared green, and nuclei expressing equivalent levels of PRA and PRB were yellow. Control sections were treated and stained in the same way as the test sections. Controls included adjacent sections to each tumor sample stained using antibody diluent (PBS/0.5% Triton X-100): (a) in place of both primary antibodies to control for nonspecific staining; and (b) to replace the second sequence primary antibody to ensure no cross-reactivity between the two staining sequences. Human colon and myometrial tissues were used for a negative and positive control, respectively.
Fluorescent Analysis.
PR staining was examined using an Olympus BX 40 fluorescent microscope fitted with filters to detect both TXR (BP 545–580) and FITC (BP 450–480) fluorescence simultaneously, and each of the two fluorochromes separately. The whole section was examined in detail under both individual fluorochrome excitations and also using the dual filter, to identify the staining intensity of the tumor, recorded as either low, moderate, or high and to describe the color of staining. All of the tumors had coexisting PR positive areas with different PR staining intensity. The predominant area, defined as comprising at least 60% of the total stained area, formed the focus of the analysis.
The relative expression of PRA and PRB was assessed by three independent observers (R. L. A. M., A. deF., C. L. C) and was determined by the level of FITC and TXR fluorescence over the entire section under single and dual excitation. Tumors that contained only one isoform were scored as PRA or PRB; tumors for which both PR isoforms were present with one in predominance were scored as PRA > PRB or PRB > PRA; tumors for which both of the PR isoforms were present in similar levels were scored as PRA = PRB.
Two distinct types of heterogeneity in the relative expression of PRA and PRB proteins were assessed: (a) adjacent cell heterogeneity, in which adjacent cells expressed markedly differing levels of PRA and PRB proteins; and (b) area heterogeneity, in which different regions within the same section showed variable levels of PRA and PRB proteins. Relative PR isoform expression and the extent of heterogeneity of relative PRA and PRB expression within a tissue were each evaluated independently.
Statistical Analysis.
Spearman’s rank correlation was used to test for association between total PR expression, FIGO grade, nuclear grade, and cell-to-cell homogeneity. Logistic regression was used to test whether there was an association between relative PR isoform expression, total PR expression, FIGO grade, nuclear grade, and cell-to-cell homogeneity; and ORs together with their 95% CIs were used to qualify these associations. Kruskal-Wallis one-way ANOVA was used to test whether the distribution of total PR expression, relative PR isoform expression, and homogeneity was similar between tumor, hyperplasia, and normal endometrial glands. Multivariate logistic regression analysis was used to test whether PR concentration and cell-to-cell homogeneity were independent predictors of PR isoform expression.
RESULTS
The cohort of endometrial cancer patients selected for this study consisted of 49 patients diagnosed with endometrioid endometrial adenocarcinoma (Table 1)
. The sections of one case were later identified as containing complex atypical hyperplasia only and, therefore, were excluded from the analysis of tumor samples but were included in the analysis of hyperplasia. The cases were de-identified before analysis. The majority of cases were stage I, and this is consistent with the relative frequency of the disease at clinical presentation. There were only four cases with stage IV tumors, consistent with the population distribution of stage; for the purpose of data analysis, stage IV was combined with stage III and termed late stage, as has been done in previous studies (9)
. FIGO grade distribution of this study is similar to the distribution of FIGO grade in previous reports (1)
. Twelve cases contained adjacent normal glands, and 11 cases contained complex atypical hyperplasia. Most of the patients were >50 years of age (87%), had BMI in the overweight or obese range (64%), and had never taken hormone replacement therapy (58%). Most patients (73%) had experienced at least one pregnancy.
Concentration of PR in Endometrial Cancers.
Most of the endometrial cancers in this cohort were PR positive [46 (96%) of 48], and PR expression was low in the majority of cases [31 (68%) of 46; Table 2
]. Adjacent areas of normal endometrium and complex atypical hyperplasia were found in a proportion of tumors and expression of PR was compared in these nonneoplastic regions. Expression of PR was significantly greater in hyperplasia and normal glands (P = 0.0001; Table 2
), compared with the tumors. The intensity of expression of PR was not significantly different in hyperplasia and normal glands, whereas PR expression in tumors was significantly different from both hyperplasia (P = 0.0007) and normal tissue (P = 0.0004; Table 2
).
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. Under dual excitation, nuclei that expressed equivalent levels of PRA and PRB were yellow (Fig. 1A)
, whereas nuclei that expressed only PRA were green (Fig. 1D)
, and those expressing only PRB were orange (Fig. 1E)
. The majority [27 (58%) of 46] of tumors expressed only one PR isoform (PRA or PRB; Fig. 1
, D or E), and the proportion that expressed either isoform was similar [PRB: 13 (28%) of 46; PRA: 14 (30%) of 46; Table 2
]. In addition to the tumors that expressed only PRA, there was a proportion of tumors [9 (20%) of 46] that expressed both isoforms, but with PRA being in marked excess over PRB, which indicated that one-half of all of the tumors expressed either PRA alone or a marked predominance of this isoform. Few tumors [10 (22%) of 46] expressed similar levels of PRA and PRB (PRA = PRB; Fig. 1A
; Table 2
), and there were no tumors that expressed both isoforms with a marked predominance of PRB.
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). PRB-only tumors were confined to those cases expressing low levels of PR. The relative expression of PR isoforms was significantly different between tumor, hyperplasia, and normal (P = 0.05; Table 2
). Cells in normal endometrial glands tended to express equivalent levels of PRA and PRB (i.e., PRA = PRB), whereas tumors and complex atypical hyperplasia expressed a predominance of one or the other isoform (Fig. 1
, J and K). Expression of PRB alone was only seen in tumor cells and not in hyperplasia or normal glands (Table 2)
. The expression of PR isoforms in hyperplasia and tumor cells was significantly different from that seen in the normal areas (Table 2)
, which suggests that alteration in relative isoform expression is an early event in the development of endometrial cancer.
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, moderate, or high homogeneity (Fig. 1E)
. Cell-to-cell expression of PR isoforms was homogeneous in most tumors [26 (57%) of 46; Table 2
]. However, there was a strong inverse relationship between homogeneity and PR expression levels (P = 0.0003; rank correlation coefficient = -0.51; Fig. 2B
); i.e., tumors that had homogeneous PR isoform expression had low overall expression of PR, whereas tumors that had heterogeneous cell-to-cell PR isoform expression tended to express higher levels of PR. Homogeneous cell-to-cell PR isoform expression was also significantly associated with expression of a single PR isoform (P = 0.004; OR, 0.22; 95% CI, 0.08–0.62; Fig. 2C
). Heterogeneity of PR isoform expression was also noted in adjacent regions (Fig. 1, G–I)
. In the example shown in Fig. 1G
, the adjacent regions were of different grades, with the upper region (PRA = PRB; Fig. 1G
) being nuclear grade 1 and the lower region (PRA > PRB; Fig. 1G
) being nuclear grade 2.
Cell-to-cell homogeneity of PR isoform expression was significantly different between tumor, hyperplasia, and normal (P = 0.02; Table 2
). Cells in normal endometrial glands displayed homogeneous expression of PR isoforms; however, the appearance of variation in cell-to-cell PR isoform expression was noted early in the endometrial disease continuum. Heterogeneity of PR isoform expression was significantly greater in hyperplasia than in normal glands (P = 0.008; Table 2
), whereas there was no significant difference between tumor and hyperplasia (P = 0.73; Table 2
).
Relationship between PR Concentration, PR Isoform Expression, and Cell-to-Cell Homogeneity of PR Isoform Expression.
There was a significant inverse relationship between PR concentration and expression of a single PR isoform, and PR concentration and cell-to-cell homogeneity of PR isoform expression. Multivariate logistic regression analysis was used to test whether PR concentration and cell-to-cell homogeneity were independent predictors of PR isoform expression. The adjusted ORs for the model showed that there was a negative association between PR concentration and expression of a single PR isoform (P = 0.008; adjusted OR, 0.11; 95% CI, 0.02–0.56), and a positive association between homogeneous cell-to-cell PR isoform expression and expression of a single PR isoform (P = 0.002; adjusted OR, 22.6; 95% CI, 3.22–157.76), confirming that these two variables were independent predictors of the expression of a single PR isoform.
Association of PR Isoform Expression with Clinical Features.
PR expression was significantly inversely related to clinical grade, with proportionally lower levels of PR being seen in higher FIGO (P = 0.02; rank correlation coefficient = -0.36) and nuclear grades (P = 0.02; rank correlation coefficient = -0.33; Fig. 3A
). Expression of similar levels of both PR isoforms was found primarily in lower-grade tumors (PRA = PRB; Fig. 3B
). Tumors of higher FIGO grade expressed one PR isoform only or a predominance of PRA, and this was statistically significant (P = 0.03; OR, 0.15; 95% CI, 0.03–0.79). There was a trend for this relationship to hold also with nuclear grade as can be seen by the absence of the PRA = PRB expression profile in nuclear grade 3 tumors (P = 0.12; OR, 0.42; 95% CI, 0.14–1.27). Cell-to-cell PR isoform expression was homogeneous in tumors with higher FIGO grade (P = 0.05; rank correlation coefficient = 0.29; Fig. 3C
) and nuclear grade (P = 0.04; rank correlation coefficient = 0.3; Fig. 3C
).
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DISCUSSION |
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PRA and PRB Expression in Endometrial Carcinoma.
Most endometrial cancers expressed only one PR isoform, either PRA or PRB, and expression of PRA only or PRB only was equally common. In addition, an additional proportion of tumors, although expressing both isoforms, showed a marked predominance of PRA, resulting in expression of PRA only, or PRA predominantly, in one-half of all endometrial cancers. Expression of one PR isoform only, or a predominance of one isoform, was found in over three-quarters of all of the tumors and was strongly associated with low tumor levels of PR, which suggests that loss of PR expression was associated with preferential loss of one isoform and consequent predominance of one PR isoform. There were no tumors expressing both isoforms with a predominance of PRB. These results show that although loss of PRA and PRB expression takes place frequently in endometrial carcinomas, loss of PRB is slightly more common overall than loss of PRA.
In the normal endometrium, PR is highly expressed in the glandular epithelium during the proliferative phase of the cycle, and this high PR expression is associated with similar PRA and PRB expression (24) ; in support of these findings, this study showed that normal areas within the tumor specimen expressed similar relative levels of PRA and PRB. Endometrial cancers had low PR expression and predominance of one PR isoform, in contrast with the patterns of PR expression seen in the normal endometrium, although, interestingly, endometrial cancers with higher PR expression, mimicking PR levels seen in the normal tissues, showed a greater likelihood of similar PRA and PRB expression levels. Loss of expression of one PR isoform was also noted in hyperplasias, and there was a statistically significant difference in relative PR isoform expression between the normal and hyperplastic areas, which suggests that loss of coordinated expression of PR isoforms is an early event in the development of endometrial cancer.
In normal endometrium, the relative expression of PRA and PRB in adjacent cells is remarkably homogeneous (24) , and this was also noted in the normal areas of the specimens examined in this study. In endometrial cancers, this homogeneity was also noted, but only in endometrial cancer expressing a single PR isoform. In contrast to the normal endometrium, cancers expressing both isoforms tended to display heterogeneous cell-to-cell levels of PR isoforms. Moreover, a comparison of normal, hyperplastic, and tumor areas showed that there was a significant increase in cell-to-cell heterogeneity of PR isoform expression in complex atypical hyperplasia and cancers, compared with normal areas. This increased cell-to-cell heterogeneity of PR isoform expression in hyperplasias suggests that it is an early event in endometrial cancer development. If loss of one PR isoform is a feature of endometrial cancer development, as suggested in this study, then heterogeneous cell-to-cell expression of both of the PR isoforms may reflect the asynchronous loss of one isoform from adjacent cells, leading eventually to homogeneous expression of a single isoform.
Endometrial hyperplasia is an acknowledged precursor of endometrial carcinoma, and recent studies have shown that there are genetic alterations in hyperplasias that increase in frequency with dysplasia grade, such that the majority of complex hyperplasias have aberrant genetic profiles (30) . The hyperplasias in this study were all of a complex type, and the findings of loss of coordinated expression of PRA and PRB and the appearance of cell-to-cell heterogeneity of PR isoform expression support the view that these changes in PR expression are early events in the development of endometrial carcinoma.
In addition to cell-to-cell heterogeneity of PR isoform expression, there was also heterogeneous expression of PR isoforms in different areas of some tumors. This was associated with a number of factors, including heterogeneity of grade within a tumor, which is a known feature of endometrial carcinoma (31) . Although the origin of biological heterogeneity in endometrial carcinomas is unknown, tumors are generally thought to be monoclonal in origin, and tumor progression is associated with increasingly altered subpopulations within the tumor, resulting in tumor heterogeneity (32) . Subsequent selection of variants with some growth or survival advantage can lead to different clones arising within the tumor (32) . The area-to-area heterogeneity of PR isoform expression may be a manifestation of this clonal evolution.
PR Expression and Clinicopathological Features in Endometrial Carcinoma.
High expression of PR was significantly associated with tumors of low grade, which are associated with good prognosis (33
, 34) , whereas low PR expression was a feature of high-grade tumors. This supports previous findings (9
, 35
, 36)
and shows that reduced PR expression is associated with poorer-prognosis tumor phenotypes.
Relative PR isoform expression was also related to tumor grade; equivalent expression of both PR isoforms was seen only in FIGO grade 1 tumors, with loss of one PR isoform, resulting in a predominance of the other isoform, being common in higher FIGO grades. The relationship between PR isoform expression and FIGO grade suggests that expression of a single PR isoform is associated with poorer prognostic features in endometrial cancer. Two studies, using cell lines as described previously (37 , 38) , indicated PRB was not expressed in poorly differentiated endometrial cancer cells, but this finding is not borne out in tumors, as shown in this study.
In the present study, there was no association between PR expression levels and surgical stage. This contradicts reports of an inverse correlation between PR expression level and stage in other studies (9 , 35 , 36) . However, the distribution of tumor grades within the clinical stages in this study was similar; e.g., the proportion of FIGO grade 1 tumors was 64% in stage I, 33% in stage II, and 50% in both stage III and stage IV tumors (not shown). Because PR expression was strongly associated with tumor grade, and the distribution of tumor grade was similar between the clinical stages, it is perhaps not surprising that no association was found with clinical stage in this study.
Taken together, the results of this study show that overall expression of PR is reduced in endometrioid endometrial cancer compared with epithelial cells of the normal endometrium and that a reduction in PR expression is accompanied by reduced expression of PRA and/or PRB. Normal endometrial cells usually coexpress both PRA and PRB (24) , and both isoforms are implicated in progesterone action in this tissue (39) . This study has shown that endometrial cancer cells commonly express only one PR isoform, and because overexpression of PRA in cultured breast cancer cells can result in altered cell response to progestins (40) , expression of one isoform in carcinomas may alter hormone action in these tissues. The mechanisms that control the relative expression of PRA and PRB are not known, but this study has revealed a descriptive association between disruption of these mechanisms and progression to malignancy. Definitive associations between PR isoform expression and endometrial carcinogenesis must await additional studies. The findings of this study, that disrupted expression of PR isoforms is an early event in endometrial cancer development and that it is associated with poorer prognostic clinical features, suggests that relative PR isoform expression is important in the maintenance of endometrial homeostasis and that its disruption may contribute to the malignant phenotype.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by the National Health and Medical Research Council of Australia, the Leo and Jenny Leukemia and Cancer Foundation, and the Westmead Millenium Foundation. 
2 To whom requests for reprints should be addressed, at Westmead Institute for Cancer Research, Westmead Hospital, Westmead, NSW 2145, Australia. Phone: 61-2-9845-9068; Fax: 61-2-9845-9102; E-mail: christine_clarke{at}wmi.usyd.edu.au
3 The abbreviations used are: PR, progesterone receptor; TXR, Texas red; OR, odds ratio; CI, confidence interval; BMI, body mass index.
Received 8/28/00. Accepted 4/ 3/01.
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSDISCUSSIONREFERENCES |
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, PRA only; 
, PRA > PRB; 
PRA = PRB; 
, PRB only. B, comparison of homogeneity of PR isoform expression and of overall PR expression levels; 