Expression of steroid receptor coactivators and corepressors in human endometrial hyperplasia and carcinoma with relevance to steroid receptors and Ki-67 expression

BACKGROUND: To examine the steroid hormone dependent growth mechanism of human endometrial hyperplasia and carcinoma, expression levels of steroid receptor cofactors, such as coactivators (steroid receptor coactivator 1 [SRC-1] and p300/cyclic AMP-response element-binding protein (p300/CBP]) and corepressors (nuclear receptor corepressor [NCoR] and silencing mediator for retinoid and thyroid-hormone receptors [SMRT]), were investigated. METHODS: The expression levels of cofactors were examined immunohistochemically using 20 samples of normal endometria, 36 samples of hyperplastic endometria, and 58 of malignant endometria and were compared with the expression levels of estrogen receptor (ER), progesterone receptor (PR), and a proliferation marker, Ki-67. RESULTS: In samples of normal endometria, the expression of coactivators was observed diffusely in glandular cells in the proliferative phase, with a mean positivity index (PI) of 81.8 for SRC-1 and 91.3 for p300/CBP, whereas expression levels decreased in endometrial hyperplasia (PI: SRC-1, 58.9; p300/CBP, 83.8) and endometrial carcinoma (PI: SRC-1, 45.0; p300/CBP, 55.4). In endometrial hyperplasia, there was a significant correlation between the expression of ER and SRC-1 or p300/CBP. In contrast, there were no significant statistical or topologic correlations between the expression of coactivators and the expression of ER/PR in endometrial carcinoma. The expression of corepressors generally was limited, except for elevated expression of NCoR in endometrial hyperplasia (PI, 23.8). CONCLUSIONS: The current study showed that expression levels of the steroid receptor coactivators SRC-1 and p300/CBP were reduced in endometrial carcinoma compared with normal and hyperplastic endometrium. In addition, topologic coexpression of both coactivators and ER/PR was lost in endometrial carcinoma. Accordingly, limited response to sex steroids in patients with endometrial carcinoma may be ascribed to the dissociation of cofactors and ER/PR.     

Regulatory mechanism of steroid hormone receptor functions

The steroid hormone receptor has been defined as an intracellular protein which associates with the corresponding ligand in a stereospecific manner. Its binding ability and affinity have been reported to be affected by many factors such as protein kinase, SH reducing agent and molybdate. Through ligand binding, hormone-receptor complexes undergo activation process resulting in its acquisition of high affinity toward DNA. Although the detailed biochemical mechanism of receptor activation remains to be elucidated, the reduction of their molecular size has been proposed to be an obligatory step for receptor activation. Recently, heat shock protein 90 K, has become known to bind with the oncogene product (pp 60 v-src). Furthermore, it has been demonstrated to be a common component of both nonactivated, and not activated steroid receptor. The recombinant gene technology has successfully determined the amino acid sequence of GR, ER and PgR. All steroid receptors consist of three domains, namely the immunogenic, DNA-binding and steroid-binding domains. Experiments using deletion mutant receptors revealed that the DNA binding domain has both abilities of DNA binding and transactivation, and that the steroid binding domain negatively regulates DNA binding activity. The purified GR has been found to bind with the specific region (GRE) of glucocorticoid-dependent genes. The consensus sequence of GRE has been observed to be TG-TTCT. Two other proteins which can be associated with some regions near GRE have been proposed to activate cooperatively the glucocorticoid responsive genes with GR. Therefore, the steroid hormone receptor systems are suitable for clarifying the molecular mechanism of gene activation.     

Reliability of steroid hormone receptor assays: an international study

The reproducibility of oestrogen and progestin receptor assays performed by laboratories participating in an international breast cancer treatment trial has been assessed. Three tissue reference powders containing low, medium and high oestrogen receptor levels (22 ± 4, 88 ± 7, 227 ± 13 fmol/mg cytosol protein respectively) were prepared in Louisville, KY, U.S.A., assayed repeatedly and multiple samples of each shipped on solid CO₂ to the coordination-distribution centre in Berne, Switzerland. Samples were dispatched from Berne to Cantons within Switzerland, to Yugoslavia, South Africa, Australia, New Zealand and also back to the United States for oestrogen and progestin receptor assays. Results were returned to Berne, Switzerland. There was a decrease in the levels of oestrogen and progestin receptors during the time of storage and transit. However, the ability to assign a powder to either the low, medium or high level of oestrogen receptor was not affected. Laboratories also determined progestin receptor. All laboratories clearly identified the powder containing the low level of progestin receptor, but there was poor quantitation with the other two assay standards. It is recommended that clinical hormone receptor laboratories, especially those participating in clinical trials, establish regular quality control procedures for both daily evaluation internally and periodic outside monitoring of interlaboratory variation.     

Time-dependent relevance of steroid receptors in breast cancer.

PURPOSE: To analyze the time-dependent prognostic role of the investigated variables, considered, when appropriate, on a continuous scale, for the purpose of evaluating and describing the interrelationships between clinically relevant patient and tumor characteristics (age, size and histology, and estrogen receptor [ER] and progesterone receptor content) and the risk of new disease manifestation. PATIENTS AND METHODS: We applied a flexible statistical model to a case series of 1,793 patients with axillary lymph node-negative breast cancer with a minimal potential follow-up of 10 years. To avoid a potential confounding effect of adjuvant treatment, only patients given local-regional therapy until relapse were considered. RESULTS: ER content and tumor size (adjusted for all the other covariates) showed a time-dependent relationship with the risk of new disease manifestations. In particular, ER content failed to show a prognostic effect within the first years of follow-up; thereafter, a positive association with risk of relapse was observed. For tumor size, within the first years of follow-up, the risk of relapse was directly related to size for only tumors up to 2.5 cm in diameter; thereafter, the impact on prognosis progressively decreased. CONCLUSION: The availability of a long follow-up on a large breast cancer series, as well as the use of innovative statistical approaches, allowed us to explore the functional relation between steroid receptors and clinical outcome and to generate a hypothesis on the involvement of ER in favoring long-term metastasis development.     

The predictive value of steroid hormone receptor analysis in breast, endometrial and ovarian cancer

The predictive value of female sex steroid, estrogen and progesterone, receptor (ER and PR, respectively) assays in breast, endometrial and ovarian cancer is reviewed with emphasis on comparative aspects of these malignant tumors in relation to their hormone dependency. The endocrine etiology of these three tumor types seems to be at least partly different, and so is the expression of these receptors in normal and malignant tissues of the breast, endometrium and ovary. There is a tendency for decreased receptor concentrations and disappearance of these receptors in association with advancement of these malignancies. There is also a decrease in the presence and concentrations of ER and PR in relation to loss of differentiation in breast and endometrial cancer. Receptor analyses have an established position in the selection of patients with advanced breast cancer for endocrine treatment, and they give promise of a similar application in endometrial cancer and in endometrioid cancer of the ovary. It is not clear whether the disease-free interval is related to the presence or concentrations of ER or PR as such in the tumor tissue. There is better survival in breast cancer patients with receptor-positive tumors, which might be due to a response to endocrine treatment. The same seems to be true for patients with endometrial cancer. Future progress in the application of female sex steroid receptor analyses in breast, endometrial and ovarian cancer needs additional controlled clinical trials and more highly developed receptor assays.     

pS2 in breast carcinoma: association with steroid hormone receptor status

AIMS AND BACKGROUND: Knowledge of the steroid hormone receptors has proved to be of significant value in breast cancer. In the present study the possible importance of estrogen-regulated pS2 protein was investigated. Our direct purpose was to answer the question whether the expression of pS2 may be a marker of functional heterogeneity with respect to the steroid hormone receptor status. METHODS AND STUDY DESIGN: The study included 152 patients with primary, operable, histologically confirmed breast carcinomas. Histology specimens were reviewed and classified according to type, nodal status, tumor size and grade. Steroid hormone receptors were assayed by biochemical methods according to the procedures recommended by the EORTC. pS2 protein measurement was performed in breast carcinoma cytosols using an immunoradiometric assay. The results were analyzed by non-parametric statistical methods. RESULTS: A statistically significant inverse correlation between pS2 protein expression and histological tumor grade was found. The expression of pS2 protein was confirmed to be correlated with steroid hormone receptor status. However, it is important to point out that in spite of these statistically significant findings there were no significant biological associations due to overlapping individual pS2 protein values. The baseline level of expression of pS2 protein was obtained in histological grade III carcinomas with a negative steroid hormone receptor status. It was shown that the distribution of carcinomas according to the baseline level of pS2 protein expression was heterogeneous among estrogen receptor-positive carcinomas, and strikingly homogeneous among estrogen and progesterone-negative carcinoma. CONCLUSION: Our study suggested that PR and pS2 protein may identify distinct subsets of estrogen receptor-positive breast carcinomas.     

Significance of immunohistochemical assessment of steroid hormone receptor status for breast cancer patients

The assessment of steroid hormone receptors in resected breast cancer tissues is essential to decide whether endocrine therapy is indicated and to select the best treatment for each patient on the basis of receptor status. Both enzyme immunoassay (EIA) and immunohistochemistry (IHC) have been generally used as methods for examination of estrogen receptor (ER) and progesterone receptor (PgR). In some patients, receptor status cannot be examined for various reasons. A questionnaire survey in Japan clarified that ER status is not examined in approximately 40% of patients receiving breast conserving surgery. To eliminate "receptor unknown" cases, IHC examination on paraffin-embedded tissue is useful to assess the in situ receptor status. The concordance rate of ER and PgR status between EIA and IHC is very high and a study of 88 cases revealed a 97.7% concordance for ER and 92.0% for PgR at a cutoff point of 10%. The cutoff point of IHC is controversial and some studies demonstrated that patients showing 1% ER positive cancer cells would benefit from endocrine therapy. On the other hand, immunohistochemical expression of receptors is heterogeneous and some patients with ER negative invasive tumors have ER positive intraductal components. A study of 65 breast cancers demonstrated that ER positive intraductal components were detected in 3.1% cases of ER negative invasive lesions. According to these results and the recommendation of the St. Gallen International Conference, IHC is thought to be more useful than EIA in the assessment of steroid hormone receptor status for breast cancer patients.     

Tumour steroid hormone synthesis and estrogen receptor status in breast cancer patients

Summary The capacity of breast cancer to synthesise active androgens and estrogens has been related to estrogen receptor (ER) status in 79 postmenopausal patients with breast cancer. Although there was no quantitative relationship between levels of ER and steroid metabolism in ER positive tumours, there was (a) a positive correlation between estrogen synthesis and ER positivity and (b) increased androgen synthesis and ER negativity. This may imply an inherent difference in the handling of hormones in ER positive and negative tumours. Address for reprints: R.C. Mason, University Department of Clinical Surgery, Royal Infirmary, Edinburgh EH39YW, United Kingdom.     

原发性肺癌的性激素受体检测及其意义

目的　研究原发性肺癌与性激素受体的关系。方法　应用免疫组化SP法对47例患者进行雌激素受体（ER），孕激素受体（PR）及雄激素受体（AR）检测。结果　原发性肺癌的ER、PR及AR阳性率分别为65．95％、61．70％及61．70％。结论　本结果显示肺癌与性激素受体有一定关系，肺癌细胞分化程度越高，性激素受体阳性率越高。通过检测了解肺癌生物学特性，提示内分泌治疗对肺癌性激素受体阳性患者有效，并对预测其预后有一定意义。     

The steroid hormone receptors in tumors of adipose tissue

The clinical evidence suggests that the steroid hormones may influence the biologic course of tumors of soft tissue. In an attempt to characterize the possible steroid hormone dependency of soft tissue, we studied the incidence and distribution of cytosolic receptors for the steroid hormones in benign and malignant tumors of adipose tissue origin. All specimens were assayed for the steroid hormone receptors by charcoal dextran technique and analyzed by the method of Scatchard. The results show a high incidence of cytosolic estrogen and glucocorticoid receptors in tumors of adipose tissue origin except in lipoma and well differentiated liposarcoma. The binding parameter of these receptors suggests that the receptors may be responsive to physiologic steroid hormonal milieu.     

Female sex steroid receptor status in primary and metastatic breast carcinoma and its relationship to serum steroid peptide hormone levels

In order to obtain more information on the interrelationships between cytosol estrogen (ER) and progestin (PR) receptors in breast carcinoma, and their distribution according to age, menopausal status and endocrine parameters of the patients, these receptors were measured in 605 primary and 150 metastatic lesions, and correlated with serum levels of estradiol, progesterone, FSH, LH and prolactin in some of these patients. Measurable estrogen receptor (> 3 fmol/mg cytosol protein) was found in 78.0% and progestin receptor (> 10 fmol/mg cytosol protein) in 60.5% of all the samples studied. The receptors were simultaneously present in 57.2%, estrogen receptor only in 20.8%, progestin receptor only in 3.3%, while both receptors were absent in 18.7% of the whole material. In samples from 253 premenopausal patients, measurable ER was found less frequently (71.1% of cases) and its concentration was lower (39.9 ± 5.1 fmol/mg cytosol protein, mean ± SEM) than in 502 postmenopausal patients (82%; 148.2 ± 11.6 fmol/mg). The frequencies of ER-positive samples and ER concentration were rather similar in primary and metastatic lesions, whereas PR was more often present (64 versus 47%) and its concentrations significantly higher (151.2 ± 12.5 versus 102.6 ± 21.1 fmol/mg) in primary than in metastatic tumors. When present simultaneously, there was a significant correlation between ER and PR concentrations in both primary and metastatic lesions independent of the menopausal status of the patient. ER concentration correlated significantly with age in both pre- and postmenopausal patients, while PR concentration correlated with age only in postmenopausal patients. The group with the highest ER values (above 100 fmol/mg cytosol protein) had a significantly lower serum estradiol concentration that the other patients. Serum estradiol values had a significantly positive correlation with cytosol PR content in the samples with a measurable PR. Serum progesterone, FSH, LH and prolactin did not correlate with tumor ER or PR concentrations. We conclude that concomitant assays of ER and PR from a breast carcinoma specimen provide a correct picture of the endocrine characteristics of the tumor independently of the serum concentrations of estradiol, progesterone, FSH, LH and prolactin.