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.     

Immunohistochemical assessment of hormone receptor status using a new scoring system (J-score) in breast cancer

The assessment of hormone receptor status in breast cancer is essential to decide whether endocrine therapy is indicated or not. Immunohistochemistry (IHC) is thought to be the best method for examination of estrogen receptor (ER) and progesterone receptor (PgR) in routine practice. However, the cutoff point of IHC is still controversial. The St. Gallen consensus meeting in 2005 demonstrated that in patients with more than 10% ER stained tumor cells, hormone therapy will be " effective " but in those with 1 to 10% ER stained tumor cells will have an " uncertain " response. Based on the cutoff value of the St. Gallen consensus meeting, a new scoring system (J-Score) which only evaluates the positivity cell rate without taking the staining intensity into account was established. In this paper, the ER status results of 486 patients evaluated by the J-Score and A-Score (Allred Scoring system) were compared. The " uncertain " patients with ER positive cells 1 to 10% (J-Score 2) composed only 0.9% and " borderline " cases (A-Score 3 to 4) including " uncertain " cases (J-Score 2) composed 3.2% of the total patients. Thus, the number of patients determined as " uncertain " by the J-Score is very small and the number considered " borderline " by the A-Score is slightly larger. Although the J-Score system is thought to be easy and convenient for evaluating ER status in routine practice and the cutoff values adjusted to St. Gallen recommendation might be meaningful for clinical studies, many pathological and clinical studies are necessary before it is accepted as a standard method.     

Immunohistochemical evaluation of hormone receptor status for predicting response to endocrine therapy in metastatic breast cancer

BACKGROUND: The importance of establishing hormone receptor status of tumors for the treatment of women with hormone receptor-positive breast cancer has been emphasized, however, there is no general agreement as to how immunohistochemical assays should be evaluated. It is critical to evaluate hormone receptor status when considering response to endocrine therapy. METHODS: Estrogen receptor (ER) and progesterone receptor (PgR) expression was examined by immunohistochemistry using Allred's score for primary breast tumors from 75 metastatic breast cancer patients who received first-line treatment with endocrine therapy (56 patients received tamoxifen, 11 patients received aromatase inhibitors, and 8 patients received LH-RH agonist or other endocrine reagents) on relapse. Correlation between hormone receptor status and response to endocrine therapy as well as post-relapse survival was analyzed. RESULTS: The most significant correlation between positive ER expression and response to any endocrine therapy (p = 0.011) or tamoxifen only (p = 0.030) occurred when the cutoff score was set at 10%. When the evaluation was based on Allred's score (TS), a cutoff point of TS>or=4 showed a more significant association between positive ER expression and response to all kinds of endocrine therapy (p = 0.020) or tamoxifen only (p = 0.047). When evaluated at a cutoff point of 1% positive cells, there were fifteen patients with both ER- and PgR-negative tumors, and three patients (20.0%) responded to the therapy. Patients with 1% or more ER or PgR positive cells had better survival after relapse (p = 0.0005 and p = 0.0008, respectively). CONCLUSIONS: The proportion score alone might be enough to predict hormone responsiveness and post-relapse survival in metastatic breast cancer. The cutoff might be set low, for example 1%, especially for metastatic disease.     

SSRI use and breast cancer risk by hormone receptor status

BACKGROUND: There is little evidence linking the use of selective serotonin reuptake inhibitors (SSRIs) with increased breast cancer risk, but one study has found an association with estrogen receptor negative (ER-) and progesterone receptor negative (PR-) tumors. METHODS: We used data collected on 820 invasive breast cancer cases and 2852 hospitalized controls collected from 1990 through 2006. Information on medication use and other variables was collected by nurse interviewers. We used unconditional logistic regression analyses to evaluate the association between regular SSRI use (use at least 4 times/week for at least 3 months) and breast cancer risk overall and by subtype defined by hormone receptor status. RESULTS: The odds ratio for all breast cancer was not elevated among regular users of SSRIs (OR = 0.89, 95% CI 0.62-1.29). None of the odds ratios varied from 1.0 in any category of hormone receptor status. Among women aged 55 and over, the odds ratios were increased for ER- (OR = 1.84, 95% CI 0.66-5.16), PR- (OR = 1.85, 95% CI 0.80-4.27), and ER-PR- (OR = 2.10, 95% CI 0.73-6.02) tumors, but these estimates were compatible with chance. CONCLUSION: We found no association between SSRI use and breast cancer risk, overall or by hormone receptor status. Odds ratios were elevated in older women, particularly for ER- and PR- tumors, but the confidence intervals were compatible with no association.     

血脂与激素受体阴性乳腺癌远处转移及疗效的关系

目的 测定激素受体阴性乳腺癌患者的血脂水平,探讨血脂异常与远处转移的关系,及化疗后血脂水平变化与近期疗效的关系。方法 收集154例激素受体阴性乳腺癌患者的临床病理资料和空腹血脂水平,远处转移组患者化疗2周期后第14天再次测定血脂水平。χ²检验分析临床病理特征及基线血脂水平与远处转移的关系,Logistic回归分析远处转移的独立危险因素,配对t检验分析远处转移组患者化疗后血脂各指标变化与疗效关系。结果 乳腺癌远处转移与肿块大小、区域淋巴结转移、组织学分级、高TC、高TG及高LDL-C血症有关(P＜0.05)。Logistic回归分析显示,肿块大小(OR=1.563)、区域淋巴结转移(OR=1.983)、高TC血症(OR=1.502)、高TG血症(OR=1.877)是远处转移的独立危险因素。远处转移组中化疗有效组(PR+SD),TC、TG及LDL-C水平有降低趋势,HDL-C水平有升高趋势,疗效PR组TG水平降低有统计学意义。结论 高脂血症与激素受体阴性乳腺癌远处转移相关,有效的抗肿瘤治疗可降低血脂水平。动态监测血脂水平可作为激素受体阴性乳腺癌远处转移及疗效评价的辅助参考指标。     

雌激素受体β蛋白在乳腺癌中表达的意义

目的:检测乳腺癌组织中雌激素受体β(ERβ)蛋白的表达情况,并分析其与乳腺癌临床病理特性的关系。方法:采用免疫组化法检测96例乳腺癌组织中ERβ蛋白的表达情况。结果:ERβ蛋白在96例乳腺癌组织标本中的阳性表达率为75·0%(72/96),癌旁组织中的阳性表达率为90·5%(57/63),二者差别具有显著性(P<0·05);ERβ蛋白表达水平与患者乳癌组织中的ERα蛋白水平、PR蛋白水平及组织学分级相关(P<0·05),与年龄、肿瘤大小、腋淋巴结转移、病理分型、绝经状态无关(P>0·05)。结论:ERβ在乳腺癌癌旁组织内广泛表达,在癌组织内亦有表达,但阳性表达率低于癌旁组织;ERβ蛋白的阳性表达可能是乳腺癌预后良好的一项参考指标。     

Age interacts with the expression of steroid and HER-2 receptors in operable invasive breast cancer

BACKGROUND: The negative association between the oestrogen receptor (ER) and the human epidermal growth factor receptor 2 (HER-2) in breast cancer travels in both directions. ER+ tumours are less likely HER-2+ and HER-2+ tumours are less likely ER+. METHODS: We studied the age-related immunohistochemical (IHC) expression of ER, progesterone receptor (PR) and HER-2 in 2,227 tumours using age as a continuous variable. Steroid receptors were considered positive for any nuclear staining of invasive cancer cells and for HER-2, either for strong expression by IHC (score 3+) or gene amplification by fluorescence in situ hybridisation (FISH). Based on nonparametric regression, the age-related association between steroid receptors and HER-2 was presented as likelihood curves. RESULTS: The association between ER or PR and HER-2 is age-related. The age-related expression of ER and PR is HER-2 dependent. In HER-2(-) cases, the odds ratio (OR) for being ER+ was 2.594 (95% CI = 1.874-3.591) up to age 50 and age-independent thereafter; for PR-expression the OR was 2.687 (95% CI = 1.780-4.057) up to age 45 and 0.847 (95% CI = 0.761-0.942) thereafter. In HER-2+ cases, the OR was 0.806 (95% CI = 0.656-0.991) to be ER+ and 0.722 (95% CI = 0.589-0.886) to be PR+. The age-related OR for breast cancers to be HER-2+ is steroid receptor dependent. Taking together, ER+PR+HER-2+ breast cancers appear on average 5.4 years earlier than breast cancers of any other ER/PR/HER-2 phenotype (95% CI = 3.3-7.5; P < 0.0001). CONCLUSION: There is a qualitative interaction between age and expression of steroid and HER-2 receptors. Our findings suggest a strong age-related selective growth advantage for breast tumour cells belonging to the ER+PR+HER-2+ subgroup.     

Impact of low estrogen/progesterone receptor expression on survival outcomes in breast cancers previously classified as triple negative breast cancers

PURPOSE:

To evaluate the impact of low estrogen/progesterone receptor (ER/PR) expression and effect of endocrine therapy on survival outcomes in human epidermal growth factor receptor 2 (HER2)‐negative tumors with ER/PR <10%, previously labeled as triple negative.

METHODS:

In a retrospective review, 1257 patients were categorized according their ER/PR percentages into 3 groups, ER/PR <1% (group A), ER/PR 1% to 5% (group B), and ER/PR 6% to 10% (group C). Kaplan‐Meier product limit method was used to estimate survival outcomes. Cox proportional hazards models was used to adjust for patient and tumor characteristics.

RESULTS

Groups A, B, and C had 897 (71.4%), 241 (19.2%), and 119 (9.4%) patients, respectively. After a median follow‐up of 40 months there was no significant difference in 3‐year recurrence‐free survival (RFS): 64%, 67%, and 77% (P = .34) or overall survival (OS): 79%, 81%, and 88% (P = .33) for groups A, B, and C, respectively. ER/PR expression was not an independent predictor for RFS (hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.86‐1.39; P = .46 for group B, and HR, 0.96; 95% CI, 0.66‐1.38; P = .81 for group C, compared with group A), or OS (HR, 1.11; 95% CI, 0.84‐1.46; P = .46 for group B, and HR, 0.94; 95% CI, 0.63‐1.42; P = .78 for group C, compared with group A). Endocrine therapy had no impact on survival outcomes (RFS: P = .10; OS: P = .45) among groups.

CONCLUSIONS:

In this cohort, a low ER/PR level (1%‐5%) does not appear to have any significant impact on survival outcomes. There was a tendency for survival advantages in the ER/PR 6% to 10% is seen. Benefit of endocrine therapy in these patients is unclear. Cancer 2011;. © 2011 American Cancer Society.     

Estrogen receptor negative/progesterone receptor positive breast cancer is not a reproducible subtype

Introduction

Estrogen receptor (ER) and progesterone receptor (PR) testing are performed in the evaluation of breast cancer. While the clinical utility of ER as a predictive biomarker to identify patients likely to benefit from hormonal therapy is well-established, the added value of PR is less well-defined. The primary goals of our study were to assess the distribution, inter-assay reproducibility, and prognostic significance of breast cancer subtypes defined by patterns of ER and PR expression.

Methods

We integrated gene expression microarray (GEM) and clinico-pathologic data from 20 published studies to determine the frequency (n = 4,111) and inter-assay reproducibility (n = 1,752) of ER/PR subtypes (ER+/PR+, ER+/PR-, ER-/PR-, ER-/PR+). To extend our findings, we utilized a cohort of patients from the Nurses’ Health Study (NHS) with ER/PR data recorded in the medical record and assessed on tissue microarrays (n = 2,011). In both datasets, we assessed the association of ER and PR expression with survival.

Results

In a genome-wide analysis, progesterone receptor was among the least variable genes in ER- breast cancer. The ER-/PR+ subtype was rare (approximately 1 to 4%) and showed no significant reproducibility (Kappa = 0.02 and 0.06, in the GEM and NHS datasets, respectively). The vast majority of patients classified as ER-/PR+ in the medical record (97% and 94%, in the GEM and NHS datasets) were re-classified by a second method. In the GEM dataset (n = 2,731), progesterone receptor mRNA expression was associated with prognosis in ER+ breast cancer (adjusted P <0.001), but not in ER- breast cancer (adjusted P = 0.21). PR protein expression did not contribute significant prognostic information to multivariate models considering ER and other standard clinico-pathologic features in the GEM or NHS datasets.

Conclusion

ER-/PR+ breast cancer is not a reproducible subtype. PR expression is not associated with prognosis in ER- breast cancer, and PR does not contribute significant independent prognostic information to multivariate models considering ER and other standard clinico-pathologic factors. Given that PR provides no clinically actionable information in ER+ breast cancer, these findings question the utility of routine PR testing in breast cancer.     

Clinical implications of high NQO1 expression in breast cancers

Background

NAD (P) H: quinone oxidoreductase 1 (NQO1) is a xenobiotic metabolizing enzyme that detoxifies chemical stressors and antioxidants, providing cytoprotection in normal tissues. However, high-level expression of NQO1 has been correlated with numerous human malignancies, suggesting a role in carcinogenesis and tumor progression. This study aimed to explore the clinicopathological significance of NQO1 and as a prognostic determinant in breast cancer.

Methods

A total of 176 breast cancer patients with strict follow-up, 45 ductal carcinoma in situ (DCIS), 22 hyperplasia and 52 adjacent non-tumor breast tissues were selected for immunohistochemical staining of NQO1 protein. Immunofluorescence staining was also performed to detect the subcellular localization of NQO1 protein in MCF-7 breast cancer cells. Eight fresh breast cancers paired with adjacent non-tumor tissues were quantified using real time RT-PCR (qRT-PCR) and western blot. The correlations between NQO1 overexpression and the clinical features of breast cancer were evaluated using chi-square test and Fisher’s exact tests. The survival rate was calculated using the Kaplan–Meier method, and the relationship between prognostic factors and patient survival was also analyzed by the Cox proportional hazards models.

Results

NQO1 protein showed a mainly cytoplasmic staining pattern in breast cancer. The strongly positive rate of NQO1 protein was 61.9% (109/176) in breast cancer, and was significantly higher than in DCIS (31.1%, 14/45), hyperplasia tissues (13.6%, 3/22) and adjacent non-tumor tissues (13.5%, 7/52). High-level expression of NQO1 protein was correlated with late clinical stage, poor differentiation, lymph node metastasis, Her2 expression and disease-free and 10-year overall survival rates in breast cancer. Moreover, multivariate analysis suggested that NQO1 emerged as a significant independent prognostic factor along with clinical stage and Her2 expression status in patients with breast cancer.

Conclusions

High-level expression of NQO1 appears to be associated with breast cancer progression, and may be a potential biomarker for poor prognostic evaluation of breast cancers.     

Steroid receptor status,proliferation and metallothionein expression in primary invasive ductal breast cancers

The most important immunocytochemical prognostic and predictive factors in cases of breast cancer include estrogen receptor alpha (ER) and progesterone receptor (PgR). The present study aimed at examining the relationship between the manifestation intensity of proliferation markers (Ki-67 and nucleolar organizer regions--AgNORs) on one hand, and expression of ER and PgR on the other in a uniform group of invasive ductal breast cancers of G2 grade. Moreover, the study aimed at examining the relationship between the above mentioned markers and expression of metallothionein (MT). The studies were performed on samples of invasive ductal breast cancers of G2 grade, originating from 60 females. In paraffin sections originating from the studied cases immunocytochemical reactions were performed using monoclonal antibodies to ER, PgR, Ki-67 and MT, and silver staining was conducted to localize AgNORs. The obtained results were subjected to statistical analysis using Statistica software. Results indicate that manifestation of AgNORs does not correlate with any of the studied antigens (ER, PgR, Ki-67, MT) (p>0.05). Moreover, no relationship could be demonstrated between the intensity of MT expression and proliferation markers or steroid receptor status (p>0.05). A negative correlation was shown between the expression of ER and Ki-67 (p=0.0009). The most intense proliferative activity was demonstrated in cases of breast cancer showing PgR expression but no ER expression (p=0.015), while the lowest proliferative activity was detected in breast cancers with expression of both ER and PgR (p<0.05).     

Triple negative breast cancer compared to hormone receptor negative/HER2 positive breast cancer

The aim of this study is to reveal likely demographic, clinical, and pathological differences among hormone receptor negative breast cancer patients according to their HER-2 status. The medical records of hormone receptor negative breast cancer patients with known HER-2 status between January 1999 and December 2006 were reviewed, retrospectively. A total of 91 cases were included in the study (68 HER-2 negative cases and 23 HER-2 positive cases). The results obtained showed that median age, menarche age, childbearing age, number of children, menopause age, and body-mass indexes were similar in both groups. The HER-2 negative patients had more family history of breast cancer than HER-2 positive patients (13.2% and 0%, respectively, P = 0.091). Eighty-three patients received neoadjuvant/adjuvant chemotherapy. Recurrence occurred in 41 (46.6%) patients. Neither recurrence nor disease-free survival of those patients was associated with HER-2 status. Tumor size (P = 0.042) and number of involved lymph nodes (P = 0.001) were found to be independent prognostic factors for disease-free survival. A tendency for more frequent cerebral metastasis was found in HER-2 positive advanced stage patients (P = 0.052). HER-2 positive patients were less responsive to taxanes (P = 0.071). The number of involved lymph nodes (P = 0.004) and HER-2 status (P = 0.043) were found to be prognostic factors for overall survival. HER-2 positive and negative patients should be followed and treated with different strategies. HER-2 positive patients are at least as resistant to systemic therapies as the HER-2 negative patients. Genetic counseling should be routinely provided to triple negative patients and their families. HER-2 positive patients may be candidates for prophylactic treatment strategies concerning cerebral metastasis.     

Immunohistochemical image analysis of estrogen and progesterone receptors in breast cancer

Background  Recently objective quantification of immunohistochemical estrogen receptor (ER) and progesterone receptor (PgR) staining in breast cancer by image cytometry has been predominantly performed by measuring the area of positively stained cells. However, in sample preparations of immunostained hormone receptors, both the stained area and the intensity of staining vary. In this study, we performed quantification of the stained area by measuring, tailing intensity using image cytometry. Methods  Quantitative analysis of ER and PgR immunohistochemistry was performed using image cytometry. The obtained values were presented as % of positive staining (%PS). Comparison of %PS with values obtained by EIA and with clinicopathological features was performed. Results  The %PS values and the natural logarithm of the EIA levels of the hormone receptors showed a significant positive correlation for both ER and PgR. The concordance of the results obtained by the two methods was 96.3% for ER and 73.7% for PgR. The ER-%PS values of postmenopausal patients were significantly higher than those of premenopausal patients, whereas the PgR-%PS values of the former group were significantly lower than those of the latter group. Conclusions  The quantification of ER and PgR in immunostained preparations using %PS as a parameter was reproducible and showed a high correlation with values obtained by EIA. It was shown that only menopausal status affects hormone receptor levels when analyzing the relationship between %PS measurements and clinicopathological features.     

雌、孕激素受体及HER-2受体在乳腺癌原发灶及复发转移灶之间的表达差异

背景与目的：乳腺癌内分泌治疗及免疫靶向药物赫赛汀生物治疗的前提是相应的雌激素受体(estrogen receptor,ER)、孕激素受体(progestin receptor,PR)的阳性表达及HER-2受体的过表达。目前对复发转移的乳腺癌病例受体表达情况的判断主要依据原发灶,而忽略了原发灶和复发转移灶之间可能存在的差异。本文着重研究ER、PR及HER-2受体在乳腺癌原发灶和复发转移灶之间的表达差异,探讨其临床意义。方法：免疫组织化学方法检测65例复发转移的乳腺癌病例中ER、PR及HER-2受体在原发灶及复发转移灶之间的表达差异。结果：ER的阳性率在原发灶和复发转移灶之间的差异有显著性,PR及HER-2受体的阳性率在两者之间的差异无显著性;ER在原发灶和复发转移灶之间总的变化率为35．4％,PR总的变化率为29．2％,HER-2受体总的变化率为16．9％。结论：ER在乳腺癌原发灶和复发转移灶之间的表达存在显著性差异。PR及HER-2受体的表达在原发灶和复发转移灶之间存在差异,虽无统计学意义,但在对复发或转移乳腺癌进行临床治疗时,仍应考虑上述三种指标在复发、转移灶里的确切状况。     

Coexistence of the loss of heterozygosity at the PTEN locus and HER2 overexpression enhances the Akt activity thus leading to a negative progesterone receptor expression in breast carcinoma

Serine/threonine kinase Akt/PKB is known to regulate divergent cellular processes, including apoptosis, proliferation, differentiation, and metabolism. Akt is activated by a variety of stimuli, through such growth factor receptors as HER2, in phosphoinositide-3-OH kinase (PI3K)-dependent manner. A loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function also activates Akt. It has recently been shown that Akt activation is associated with a worse outcome among endocrine treated breast cancer patients and that it also inhibits the progesterone receptor (PR) expression via the PI3K/Akt pathway in breast cancer cells. Therefore, the PI3K/Akt signaling pathway has recently attracted considerable attention as a new target for effective therapeutic strategies. In the present study, we investigated the relationship between Akt activation and either HER2 overexpression or PTEN gene alteration, as well as the PR expression. We analyzed the incidence of LOH at the PTEN locus in 138 breast cancer patients, using our new system for microsatellite analysis, called high-resolution fluorescent microsatellite analysis (HRFMA). We showed Akt activation to significantly correlate with HER2 overexpression or LOH at the PTEN gene locus while inversely correlating with the PR expression. In addition, when LOH at the PTEN gene locus and HER2 overexpression occurred simultaneously, the incidence of Akt activation and reduced PR expression was significant. The association between Akt activation and PR negative expression was observed even in the ER-positive cases. Our results suggest that simultaneous PTEN LOH and HER2 overexpression enhances Akt activation and may thus lead to a negative PR expression. This study was supported by grants from the Ministry of Education, Culture, Sports Science, and Technology of Japan.     

Immunohistochemical assessment for estrogen receptor and progesterone receptor status in breast cancer: Analysis for a cut-off point as the predictor for endocrine therapy

BACKGROUND: An immunohistochemical (IHC) method is commonly used for determining estrogen receptor (ER) and progesterone receptor (PR) status in breast cancer. However, the proper cut-off points of IHC have not been established. Cut-off points for ER and PR status as predictive factors for endocrine therapy are needed. METHODS: A total of 249 cases of female breast cancer were enrolled. ER and PR status by IHC were analyzed using the proportion of stained cells and staining intensity by Allred's score. RESULTS: Proportion score (PS) and intensity score (IS) were related to enzyme immunoassay (EIA) titers, for both in ER and PR (p < 0.0001, all). PS correlated with IS in both ER and PR (R = 0.47 and 0.41, respectively). ER status by IHC was related to tumor size and lymph node status, while PR was related to tumor size and menopausal status. In 152 patients who received endocrine therapy with a median follow-up term of 38 months, differences in disease-free survival were most significant using a cut-off point of PS 3 which indicated more than 10 % of cells stained positively for both ER and PR (p = 0.0007 and 0.0087, respectively). In addition, combination analysis of ER and PR using this cut-off point revealed a notable prognostic difference. CONCLUSION: A 10 % staining proportion may be an acceptable cut-off point for both ER and PR status by IHC, in terms of predicting response to endocrine therapy in breast cancer.     

Clinical impact of assay of estrogen receptor beta cx in breast cancer

Since 1996 when estrogen receptor beta(ER beta) was discovered, much effort has been devoted to the question of the value of ER beta as a prognostic and/or predictive factor in breast cancer and its potential as a novel target for pharmacological intervention. When estrogen receptors are applied on sucrose gradients and quantified by ligand binding, we found that in contrast to ER alpha, which has a narrow tissue distribution, ER beta is expressed in many tissues including both normal and malignant breast tissue. Receptor protein levels in tissues can also be measured from the intensities of bands after Western blotting and can be quantified when purified and quantified receptor is used as a standard. With this technique, we found that there were some tumors which had over 600 fmol/mg of ER beta protein but no detectable estradiol binding. In such tumors, RT-PCR analysis revealed that ER beta cx is the only ER beta isoform present. ER beta cx is a splice variant which utilizes an alternative exon 8. This change in the C-terminus results in very poor binding to estradiol (E2) and has a dominant negative effect on ER alpha function. Immunohistochemical analysis with an ER beta cx specific antibody in 115 ER alpha-positive breast cancers revealed that about half of the samples expressed ER beta cx protein. Initial analysis of samples from patients with preoperative tamoxifen treatment revealed that ER alpha-positive tumors expressing ER beta cx and lacking PR seemed to be resistant to the anti-estrogen. We conclude that, in order to better characterize breast cancers and design appropriate therapy for individual patients, assays for ER beta cx must be made available to clinicians.     

单激素受体阳性乳腺癌患者的临床病理特征及预后因素分析

目的分析雌激素或孕激素受体阳性即单激素受体阳性乳腺癌患者的临床病理特征及预后因素,比较两种单激素受体阳性即ER单阳性和PR单阳性乳腺癌患者的不同之处。方法2000年9月至2002年9月在我院就诊的Ⅰ～Ⅲ。期单激素受体阳性乳腺癌患者共112例,分析其临床病理特征及预后因素。结果全组患者5年生存率（OS）为89．0％,5年无病生存率（DFS）为79．8％。COX多因素预后分析显示,腋窝淋巴结转移数目是全组患者的独立预后因素（P=0．003）,脉管瘤栓是淋巴结阴性单激素受体阳性患者DFS的独立预后因素（P=0．038）。PR单阳性组年龄≤50岁（P=0．021）以及绝经前患者（P=0．033）显著多于ER单阳性组。PR单阳性组分级3级、肿瘤直径〉2cm、脉管瘤栓者的比例略高于ER单阳性组,但无统计学意义。内分泌治疗可显著改善ER单阳性组患者的OS（P=0．04）及DFS（P=0．000）。内分泌治疗有一定程度上提高了PR单阳性组患者的OS（P=0．271）及DFS（P=0．387）。结论腋窝淋巴结转移数目是全组患者的独立预后因素。内分泌治疗可显著改善ER单阳性组患者的生存,有改善PR单阳性组患者生存的趋势。