Oestrogen receptor beta expression and depth of myometrial invasion in human endometrial cancer

We assessed the relative expression of oestrogen receptor (ER)alpha and oestrogen receptor (ER)beta mRNAs in 36 human endometrial cancers using a multiplex polymerase chain reaction (PCR). To determine whether or not the expression of ER subtypes in endometrial cancers is associated with clinicopathological parameters, we examined correlations between ER subtypes and age, tumour grade and depth of myometrial invasion. Using multiple regression analysis, myometrial invasion showed a significant correlation with ER-beta: ER-alpha ratio (r = 0.54, P = 0.0007). The ER-beta:ER-alpha ratio was high in advanced invasive carcinoma. Western blotting analysis showed that ER-beta proteins were highly expressed in comparison with ER-alpha proteins in endometrial cancer with severe myometrial invasion. Our results suggest that ER-beta is important in the progression of myometrial invasion.     

Clinical implications of the expression of estrogen receptor-alpha and -beta in primary and metastatic lesions of uterine endometrial cancers

Novel human estrogen receptor (ER)-beta was identified in cDNA libraries from human testes. ER-beta specifically expresses in the testis, ovary, thymus, spleen, osteoblasts, fetus and uterine endometrium. ER-beta might not conserve the same physiological functions as does ER-alpha. Therefore, expressions of ER-alpha and ER-beta mRNAs in primary and metastatic lesions of uterine endometrial cancers were investigated. The levels of ER-beta mRNA were significantly lower than those of ER-alpha mRNA in uterine endometrial cancers and in normal uterine endometria. The ratio of ER-beta to ER-alpha mRNA in most primary uterine endometrial cancers was similar to that in normal uterine endometria (<0.4% of ER-beta mRNA to ER-alpha mRNA). On the other hand, in 14 of the 20 lymph node metastasis-positive cases of uterine endometrial cancers, the ratio in the metastatic lesion was significantly higher than that in the primary lesion of the corresponding case, and patient prognosis in these cases was extremely poor. Therefore, it is suggested that the intact synchronized expression of ER-beta interacting with ER-alpha might be disrupted, especially in most metastases of uterine endometrial cancers, leading to poor patient prognosis related to estrogen refractoriness.     

Quantitative analysis of estrogen receptor-alpha and -beta messenger RNA expression in breast carcinoma by real-time polymerase chain reaction

BACKGROUND: Estrogen action is mediated not only through a classic estrogen receptor (ER) (ER-alpha) but also through a second ER (ER-beta) that has a structure and function similar to ER-alpha. A correlation between ER-beta mRNA expression with ER and progesterone receptor (PR) protein levels as well as prognostic factors remains to be established in breast carcinoma. METHODS: The authors conducted a quantitative analysis of ER-alpha and ER-beta mRNA expression in 116 breast tumors using real-time polymerase chain reaction (PCR), and investigated a possible correlation between ER-alpha and ER-beta mRNA expression and ER and PR status as determined by enzyme immunoassay as well as with various prognostic factors. RESULTS: ER-alpha mRNA levels were significantly (P < 0.01) higher in ER positive compared with ER negative tumors. Conversely, ER-beta mRNA levels were significantly (P < 0.01) lower in ER positive compared with ER negative tumors. Accordingly, the ratio of ER-beta to ER-alpha was significantly (P < 0.01) higher in ER negative compared with ER positive tumors. A subset analysis based on ER and PR status showed that ER-beta mRNA levels as well as the ratios of ER-beta to ER-alpha mRNA level were highest in ER negative and PR negative tumors (P < 0.05). ER-alpha mRNA levels were significantly (P < 0.05) higher in postmenopausal compared with premenopausal tumors. Histologic Grade 3 tumors showed a significant decrease in ER-alpha mRNA levels compared with Grade 1 and 2 tumors (P < 0.01 and P < 0.05, respectively). No significant correlation between ER-alpha and ER-beta mRNA levels and histologic type, tumor size, or lymph node status was observed. CONCLUSIONS: An absolute and relative increase in ER-beta mRNA levels in ER negative and PR negative breast tumors, which rarely respond to endocrine therapy, suggests the possible involvement of up-regulation of ER-beta mRNA in the development of estrogen-independent tumors.     

子宫内膜癌组织雌、孕激素受体测定及其临床意义

目的:探讨子宫内膜癌组织雌激素受体(ER)和孕激素受体(PR)与临床病理特征的关系。方法:采用葡聚糖-活性炭吸附法(DCC法)对68例子宫内膜癌组织进行ER、PR测定,同时采用免疫组化法对其中30例进行ER、PR检测。结果:DCC法检测ER、PR的阳性率分别为79·4%和77·9%,免疫组化法均为86·7%。两种测定方法比较,ER与PR的总符合率分别为82·4%和85·7%。免疫组化法可在DCC法基础上进一步明确组织来源。ER、PR水平与组织学分级呈负相关。组织类型中腺癌(包括乳头状腺癌)与腺棘癌的ER、PR水平高于其他癌。ER水平与肥胖呈正相关。结论:ER、PR水平与组织学分级、组织学类型均反映了子宫内膜癌的生物学行为,ER、PR的测定对估计预后和临床选择激素治疗具有重要意义。     

PPARγ ERα和ERβ在子宫内膜癌的表达及其相关性分析

  目的   探讨PPARγ、ERα和ERβ在子宫内膜癌的表达情况,分析三者之间的相互联系及临床意义。   方法  采用免疫组织化学法及Western blot法检测正常子宫内膜及高中低分化子宫内膜癌组织中PPARγ、ERα和ERβ的表达。   结果  PPARγ在子宫内膜癌中表达量明显降低,且随病理分级的进展,呈递减趋势;ERα在正常子宫内膜及高分化子宫内膜癌中表达量无显著性差异（P>0.05）,而在中、低分化子宫内膜癌中表达量降低（P < 0.05）;ERβ表达量仅在低分化子宫内膜癌降低,在正常子宫内膜及高中分化子宫内膜癌中表达量无显著性差异（P>0.05）。Pearson相关分析提示ERα与PPARγ在不同子宫内膜组织中表达量呈正相关（P < 0.05）,而ERα与ERβ、ERβ与PPARγ间无相关性。   结论  PPARγ及ERα表达水平与子宫内膜癌的分化程度、临床分期相关,在子宫内膜癌的发生发展中可能起重要作用。      

K-ras mutation in tamoxifen-related endometrial polyps

BACKGROUND: K-ras mutation is thought to occur at an early stage of neoplastic progression in the endometrium. The authors investigated mutations in codon 12 of K-ras in tamoxifen (TAM)-related endometrial polyps. METHODS: DNA was extracted from 11 frozen endometrial polyps from TAM-treated patients with breast carcinoma. Mutations were detected using the mutant allele-specific amplification method. The results subsequently were analyzed for correlations with immunohistochemical data that were obtained using antibodies against estrogen receptors (ERs; alpha and beta forms), progesterone receptors (PRs; A and B forms), and Ki-67. RESULTS: Mutations in codon 12 of K-ras were observed in 7 of 11 TAM-related endometrial polyps. Expression levels of ER-alpha and PR-B were high in the glandular epithelium and low in the stroma. PR-A expression was high in both the glandular epithelium and the stroma. In the glandular epithelium, expression of ER-beta appeared to be lower than expression of ER-alpha. The Ki-67 index in the glandular epithelium ranged from 2 to 38, whereas the index ranged from 0 to 4 in the stroma (P < 0.01). CONCLUSIONS: The incidence of mutations in codon 12 of K-ras in TAM-related endometrial polyps (64%) was greater than the incidence of these same mutations in sporadic endometrial hyperplasias (4.5-23%). High expression levels of ER-alpha, PR-A, and PR-B in the glandular epithelium were observed in all polyps, regardless of K-ras codon 12 mutation status and Ki-67 index. The authors' findings may support the hypothesis that the polyp-carcinoma sequence partly indicates the development of endometrial carcinoma in postmenopausal women who have been treated with TAM.     

端粒酶hTERT在子宫内膜癌中的表达及意义探讨

目的　探讨端粒酶hTERT基因蛋白表达与子宫内膜癌发生发展的关系及对内膜癌诊断、预后的临床意义。方法　采用免疫组化方法对 33例子宫内膜癌、36例绝经期子宫内膜及 36例子宫内膜增生过长标本进行端粒酶hTERT、雌激素受体ER及孕激素受体PR检测 ,同时与正常增殖期 ,分泌期子宫内膜进行对照。结果　hTERT在子宫内膜癌中的表达强度明显高于其他内膜病变 ,有显著性差异 (P<0 .0 5 ) ;hTERT在子宫内膜癌中的表达与肌层浸润及临床分期呈正相关 ;与病理分级及雌、孕激素受体ER ,PR呈负相关。结论　上述结果提示端粒酶hTERT在子宫内膜癌的发生发展中可能起重要作用 ,端粒酶hTERT与ER ,PR的联合检测可能成为子宫内膜癌判断预后的一个指标。     

p27, cyclin E,and CDK2 expression in normal and cancerous endometrium

The objective was to investigate the immunohistochemical expression of p27, cyclin E, and CDK2 in normal and cancerous endometrium. Expression of p27 in premenopausal normal endometrium was significantly higher than that in postmenopausal normal endometrium (p=0.019). A significantly lower amount of p27 staining was observed in endometrial cancer tissues from premenopausal women than in normal premenopausal endometrium (p=0.015). Cyclin E expression in premenopausal normal endometrium was significantly higher than that in postmenopausal normal endometrium (p=0.003). A significantly higher amount of cyclin E staining was observed in endometrial cancer tissues from postmenopausal women than in normal postmenopausal endometrium (p=0.017). Regarding menopausal status, no significant difference in CDK2 staining was observed between cancerous and normal endometrium. There was a positive significant correlation between cyclin E and CDK2 expression levels in endometrial cancers (p<0.05). Western blot analysis confirmed elevated p27 protein levels in samples with positive p27 immunostaining. Considerable levels of p27 mRNA were detected in all normal and cancerous samples examined by semi-quantitative PCR. No significant relationship was found between telomerase activity and its association with p27 and cyclin E expression in endometrial cancers. These findings suggested that the decreased expression of p27 caused by post-translational mechanism might play an important role in endometrial cancer development in premenopausal women. In addition, increased cyclin E expression may play an important role in endometrial cancer development in postmenopausal women.     

p27 kipl蛋白与雌、孕激素受体在子宫内膜组织中的表达及其意义

 目的　探讨 p2 7kipl、雌激素受体 (ER)与孕激素受体 (PR)在子宫内膜癌中的表达及意义。方法　用免疫组化法检测 6 6例子宫内膜癌、2 9例子宫内膜非典型增生病变和 31例正常子宫内膜组织中p2 7kipl蛋白及其癌组织中ER和PR的表达。结果　在癌组织中p2 7kipl的表达率为 5 3.0 % ,明显低于非典型增生病变的 75 .8%和正常子宫内膜的 87.1% ,并与其分级有关 ;ER和PR的表达与p2 7kipl相似。结论　p2 7kipl与此癌的发展和恶性程度有关 ,这对其治疗和预后有参考价值。     

Expression of ps2 protein in endometrial carcinomas: Correlation with clinicopathologic features and sex steroid receptor status

Using immunohistochemistry, we examined pS2 expression in 64 samples of endometrial carcinoma, 11 samples of endometrial hyperplasia and 15 samples of normal endometrium, and compared them with clinicopathological data, estrogen receptor (ER) expression and progesterone receptor (PR) expression. Of the 64 samples of endometrial carcinoma, 45 (70%) expressed the pS2 protein. The average age of the patients with pS2-positive carcinomas (54.8 ± 8.6 years) was significantly lower than that of the patients with pS2-negative carcinomas, and all premenopausal patients were positive for the pS2 protein. Among histological types, pS2 expression was observed in 33 (92%) of the 36 G1 carcinomas, but in none of the 5 nonendometrioid carcinomas. Of the 48 ER-positive carcinomas, 43 (90%) were pS2-positive and 5 were pS2-negative. Of the 40 PR-positive carcinomas, 37 (93%) were positive for pS2. There were significant associations between pS2 expression and ER/PR expression (p < 0.001). Staining of the pS2 protein was also observed in the samples of normal endometrium. We found a progressive increase in immunoreactivity of pS2 protein from normal endometrium to endometrial hyperplasia and still more in well-differentiated carcinoma. All 11 cases of endometrial hyperplasia were strongly positive for pS2. Furthermore, patients with pS2-positive carcinomas had a better survival rate than those with pS2-negative carcinomas (p < 0.05). Our data suggest that pS2 expression is likely correlated with estrogen-related endometrial carcinoma and is possibly involved in early disease progression. Int. J. Cancer 74:237-244, 1997. © 1997 Wiley-Liss, Inc.     

The association between c-fos and c-jun expression and estrogen and progesterone receptors is lost in human endometrial cancer.

In normal human endometrium, expressions of the proto-oncogenes c-fos and c-jun parallel. We have previously shown that the expression of c-jun is related to proliferation and estrogen receptor (ER) status in endometrial epithelial cells. In this study, we analyzed endometrial cancer tissues for c-fos and c-jun messenger RNA (mRNA) expression by Northern blotting. Proto-oncogene expression was compared with ER and progesterone receptor (PR) status and with the proliferation marker Ki-67, as well as with histological grade and the use of hormone-replacement therapy (HRT). Messenger RNA for c-fos was detected in 35 of 37 cancer tissues and mRNA for c-jun in 37 of 40 tissue samples studied. No correlation was observed between the relative mRNA levels of c-fos and c-jun, suggesting distinct control mechanisms, if any, in endometrial cancer. In contrast to normal endometrium, there was no correlation between the proto-oncogene expression and Ki-67, ER or PR immunoreactivity. Neither were there any correlations between c-fos or c-jun expression and the histological grade of the tumor or preceding HRT. Our results reveal the loss of association between proto-oncogene expression and ovarian steroid receptors or cell proliferation in malignant endometrium. This gives further support to the hypothesis that alterations in estrogen and progesterone signalling pathways are involved in the pathogenesis of endometrial cancer.     

Coordinate expression of Cdc25B and ER-alpha is frequent in low-grade endometrioid endometrial carcinoma but uncommon in high-grade endometrioid and nonendometrioid carcinomas

Overexpression of cdc25B, an important cell cycle regulator, has been shown to result in mammary gland hyperplasia in transgenic mice and to increase steroid hormone responsiveness as a direct coactivator of the estrogen receptor (ER). We investigated the potential role of cdc25B in the pathogenesis of endometrial carcinomas in conjunction with ER-alpha. We examined the expression of cdc25B and phosphorylated ER-alpha in 4 archived human specimens of normal endometrium; 7 endometrial hyperplasia with or without atypia; 32 endometrioid endometrial carcinoma (EEC), including 20 low-grade (grade 1) and 12 high-grade (grade 2 or 3) tumors; and 18 endometrial cancers with aggressive histological subtypes (uterine papillary serous carcinoma and clear cell carcinoma, UPSC/CCC) by immunohistochemistry with monoclonal antibodies. Expression of cdc25B and phosphorylated ER-alpha was increased in endometrial hyperplasia and atypical hyperplasia compared with normal secretory endometrium. Ninety percent (18 of 20) of the low-grade EEC expressed cdc25B at a high level, whereas only 42% (5 of 12) of the high-grade EEC did so (chi(2) = 8.7; P < 0.01). Sixty-five percent (13 of 20) of the low-grade EEC expressed phosphorylated ER-alpha at high levels, but only 17% (2 of 12) of high-grade EEC did so (chi(2) = 7.0; P < 0.01). Coordinate high-level expression of phosphorylated ER-alpha and cdc25B occurred in 65% (13 of 20) of low-grade EEC but in only 17% (2 of 12) of the high-grade EEC (chi(2) = 7.0; P < 0.01). In the UPSC/CCC tumors, only 22% (4 of 18) of the tumors expressed phosphorylated ER-alpha at high-levels. However, 83% (15 of 18) of these carcinomas showed high expression of cdc25B (chi(2) = 13.5; P < 0.01). The majority of the UPSC/CCC (15 of 18) did not show coordinate high expression of phosphorylated ER-alpha and cdc25B. Our findings show that in endometrial hyperplasia and low-grade EEC, coordinate increase in cdc25B and phosphorylated ER-alpha occurs. However, in UPSC/CCC, cdc25B is highly expressed without coordinate increase in phosphorylated ER-alpha. Cdc25B may play important roles in the development and progression of EEC and UPSC/CCC by different mechanisms.     

雌、孕激素受体在子宫内膜良恶性肿瘤组织中的表达及其意义

目的 检测分析雌激素受体(ER)、孕激素受体(PR)在子宫内膜良恶性肿瘤组织中的表达情况,探讨ER、PR与子宫内膜癌发生、发展的关系.方法 采用免疫组织化学SP法对58例子宫内膜癌、37例子宫内膜非典型增生,25例子宫内膜单纯性增生,25例正常子宫内膜标本进行ER和PR的检测.结果 ER、PR的阳性表达率在正常子宫内膜分别为24.0%、20.0%;单纯性增生52.0%、44.0%;非典型增生70.3%、64.9%;子宫内膜癌62.1%、56.8%.正常内膜到单纯型增生及非典型增生阳性表达率呈阶梯样上升,子宫内膜癌略低于非典型增生,两者均明显高于正常内膜(P＜0.05).子宫内膜癌ER、PR强阳性表达率在不同组织分级中高分化Ⅰ级53.8%、53.8%;中分化Ⅱ级27.8%、22.2%,低分化Ⅲ级7.1%、0,低分化低表达.高分化高表达,Ⅰ级与Ⅲ级差异有统计学意义(P＜0.05).ER、PR强阳性表达率在年龄≤50岁患者41.9%、38.7%,＞50岁25.9%、22.2%,≤50岁组高于＞50岁组,但差异无统计学意义.临床各分期之间差异无统计学意义(P＞0.10).结论 正常子宫内膜到非典型增生、癌变过程中出现ER、PR异常高表达.ER、PR表达高低与癌组织分化程度密切相关,可能与子宫内膜癌的发生、预后有一定关系.