Clinical significance of bcl-2 gene expression in human breast cancer tissues

The expression of estrogen receptor (ER) and bcl-2(Bcl-2), an apoptosis protective oncogene, in normal andcancerous breast duct epithelia was immunohistochemically examined infresh frozen tumor tissues from 142 Japanese breastcancer patients. The clinico-pathological characteristics and the diseasefree survival of the patients were analyzed. Theexpression of both the proteins was also observedin intraductal components of breast cancer. Although lessthan 1% of normal duct epithelia expressed ER,Bcl-2 was diffusely expressed. The expression of boththese proteins in breast cancer significantly correlated witheach other. Their expression significantly correlated negatively withtumor size but not with lymph node status.The papillo-tubular sub-type of invasive ductal carcinoma expressedBcl-2 significantly more frequently than the solid-tubular sub-type.Patients with Bcl-2 expressing tumors survived without recurrencesignificantly more than those with tumors exhibiting reducedexpression. Papillary-cribriform type intraductal componentsexpressed both those proteins more often than the solid-comedo type.     

乳腺癌中BI-1基因的表达及其意义

Objective: To investigate the correlations of expression of Bax inhibitor-1 (BI-1) gene and the receptors of estrogen and progestogen in breast cancer and its significance. Methods: immunohistochemical methods had been used to detect the expressions of BI-1 gene and receptors of estrogen and progestogen in breast cancer. Results: The positive rates of expressions of BI-1 gene, estrogen receptor (ER) and progestogen receptor (PR) in breast cancer were 77.08%, 60.42% and 54.17%, respectively. The positive rate of expression of BI-1 gene was higher in the group with negative expression of ER than the positive group, their positive rates were 76.92% and 52.27%, respectively; but there was no statistical difference between the two groups with positive and negative expressions of PR. The positive rate of expression of BI-1 gene was also higher in the group with positive lymph node metastasis than the non-lymph node metastasis group, and their positive rates were 64.58% and 36.36%, respectively. The difference was statistically significant (P ＜ 0.05). Conclusion: BI-1 gene, in combination with ER, has guiding significance for patients with breast cancer to choose individual chemotherapy and radiotherapy after operation and can become an important indicator for judging the prognosis of breast cancer.     

Expression of c-erbB2, cyclin D1 and estrogen receptor and their clinical implications in the invasive ductal carcinoma of the breast

BACKGROUND: C-erbB2 and estrogen receptors (ER) are well known for their cell proliferative capacity. Cyclin D1 is a major downstream target of both c-erbB2 and ER. This study was designed to analyze the expression of c-erbB2, cyclin D1 and ER and their prognostic implications in invasive ductal carcinoma of the breast. METHODS: The c-erbB2 status was evaluated by fluorescence in situ hybridization and immunohistochemistry (IHC) and cyclin D1 and ER were evaluated by IHC in 333 invasive breast cancer specimens. RESULTS: The results of FISH and IHC for c-erbB2 showed 86.7% concordance. The overexpression of c-erbB2 was associated with the high expression of cyclin D1 and the negative expression of ER (P < 0.01 for both). The high expression of cyclin D1 was associated with the positive expression of ER (P < 0.01). When the group of patients who overexpressed c-erbB2 were analyzed, the patients with the low expression of cyclin D1 showed a significantly higher mortality than those with the high expression of cyclin D1 (RR = 3.2; 95% CI, 1.6-6.6). When the group of the high cyclin D1 expression was analyzed, the patients with negative expression of ER showed a significantly higher mortality than those with the positive expression of ER (RR = 2.1; 95% CI, 1.1-3.8). CONCLUSIONS: Higher expression of cyclin D1 was associated with better prognosis in patients with c-erbB2 overexpression, and positive expression of ER was associated with better prognosis in patients with high cyclin D1 expression.     

Prognostic value of c-erbB2 expression in breast cancer

BACKGROUND AND OBJECTIVES: An overexpression of c-erbB2 has been reported to be associated with a poor clinical outcome in breast cancer, however, its prognostic value remains controversial especially in patients with node negative breast cancer, and regarding the estrogen receptor (ER) status. METHODS: Immunohistochemical staining for c-erbB2 was performed on the primary breast cancer from 698 Japanese patients with a mean follow-up duration of 54 months. RESULTS: The c-erbB2 expression was positive in 120 (17.2%) of 698 cases, which inversely correlated with the ER status. Both univariate and multivariate analyses indicated the c-erbB2 expression to be a significant prognostic factor for the disease-free survival (DFS) and overall survival (OS), while the same effect was also seen in the patient groups with node negative as well as node positive breast cancer. A univariate analysis also indicated a subgroup with the positive c-erbB2 and negative ER to have both a worse DFS and OS than the other subgroups. The patients with positive c-erbB2 had a significantly worse DFS and OS than the patients with negative c-erbB2 in all patient groups stratified according to the adjuvant therapies, while the prognostic significance of c-erbB2 on DFS was also found in the patients with the node negative breast cancer who received adjuvant tamoxifen alone. CONCLUSIONS: The c-erbB2 expression is an independent significant factor for breast cancer and the prognostic significance remains in the node negative as well as node positive breast cancer, while the same effect was also found in all subgroups stratified according to the adjuvant therapies. In addition, the combination of c-erbB2 and ER made it possible to identify the subgroup with the worst clinical outcome.     

乳腺增生病雌、孕激素受体表达及临床意义

目的:探讨乳腺增生病变组织中雌、孕激素受体表达情况,及其临床意义。方法:将乳腺增生病患者手术切除标本,常规福尔马林固定,石蜡包埋,采用免疫组化S-P法,测定ER、PR表达。结果ER和PR总阳性率74.36%(27/39)和87.18%(34/39),ER、PR同时阳性为66.67%(26/39)。本组不典型增生6例ER和PR阳性率均为100%,其表达强度最强,其次为腺病伴腺瘤形成,最弱为小叶增生。结论:乳腺增生病变组织中ER、PR虽然呈高表达,是三苯氧胺(TAM)治疗的适应症,但仍有25.64%的患者ER呈阴性表达,因此,用TAM治疗乳腺增生病前应检测患者的ER和PR,阳性者可用TAM治疗。     

Luminal A型乳腺癌的激素受体表达与绝经的相关性

目的探讨Luminal A型乳腺癌的激素受体表达水平与绝经的相关性,进一步认识该类乳腺癌的生物学特性。方法回顾性分析江苏省肿瘤医院2009年1月至2012年10月收治的135例LuminalA型乳腺癌患者的雌激素受体（estrogenreceptor,ER）及孕激素受体（progesteronereceptor,PR）的表达水平（高表达（H）〉50％;低表达（L）≤50％）,比较ER、PR的不同表达分组在绝经前后患者中的差异及ER、PR间的相关性。结果绝经前LuminalA型乳腺癌ER—H／PR-H表达最常见（63．8％）;ERH／PR—L表达在绝经后患者中最常见（51．1％）,在绝经前少见（17．0％）。ER、PR的相关性在绝经前比绝经后更明显（P值：0．003VS．0．047）。结论绝经前后的LuminalA型乳腺癌患者存在ER、PR的不同表达的差异性分布,体内雌激素水平可能是引起差异的原因。     

Identification and meta-analysis of a small gene expression signature for the diagnosis of estrogen receptor status in invasive ductal breast cancer

In breast cancer, the determination of estrogen receptor (ER) expression is crucial for the decision on therapeutic strategies. Current ER expression analysis is based on immunohistochemical (IHC) staining of ER on formalin fixed tissue sections. However, low levels of ER expression frequently escape detection because of varying sensitivities of routine histopathological laboratories. Moreover, in estimating ER by IHC the receptor protein only is tested instead of the complex underlying ER pathway, which reflects its biological activity. To overcome this limitation, we have used the microarray technology to study 56 samples of invasive ductal carcinoma. We infer a robust and reliable signature of 10 genes, which is associated with ER expression and presumably therapeutically relevant biological processes. In a meta-analysis, the signature was tested on 3 further independent microarray gene expression data sets, covering different laboratories, array platforms, and clinics. The classification based on the signature showed a very low misclassification rate. In summary, the expression of few genes is sufficient to determine ER status. Future decisions on antiestrogen based therapy in breast cancer could be based on this signature rather than on immunostaining alone.     

Prognostic implication of labeling index versus estrogen receptors and tumor size in node-negative breast cancer

Summary The paper analyzes the relation among tumor size (T), estrogen receptor (ER) status, and labeling index (LI) and their relative merits in predicting the relapse-free (RFS) and overall survival (OS) in 215 node-negative women with primary breast cancer. All patients were subjected to Halsted or modified radical mastectomy; none received postoperative irradiation or systemic adjuvant therapy. The 5-year RFS was 75.3% and OS 89.0%When singly tested, LI and ER were able to significantly predict RFS and OS. In contrast, T influenced only RFS but not OS. The multivariate analysis showed that, in the presence of the two other variables, only LI retained its prognostic significance both for time to relapse (p = 0.0044) and survival (p = 0.035). From the present findings, LI appears to be a new important prognostic variable in the selection of high risk patients for whom adjuvant systemic therapy should perhaps be part of their primary treatment.Presented in part at the Annual Meeting of the American Socicty of Clinical Oncology, May, 1985, Houston, Texas, USA.     

ER和PR阴性乳腺癌雄激素受体与HER2表达相关性及其临床意义

目的 激素受体阴性(ER-/PR-)乳腺癌具有明显的肿瘤异质性,临床治疗手段相对有限.本研究探讨激素受体阴性乳腺癌组织中,雄激素受体(androgen receptor,AR)和HER2表达的相关性,及其与临床病理参数和预后的相关性.方法 收集中国人民解放军福州总医院经手术治疗并病理确诊的乳腺癌120例,中位年龄52岁.采用FISH法检测收集的激素受体阴性乳腺癌组织HER2/neu基因状态,分为HER2阳性(HER2过表达组)和HER2阴性(三阴组)两组,每组60例.并采用EliVisionTM plus免疫组化法检测AR、Ki-67、EGFR表达,分析HER2和AR表达与临床病理参数、3年无病生存期(disease free survival,DFS)的相关性.结果 AR在激素受体阴性乳腺癌组织阳性率为61.67％(74/120),HER2过表达组和三阴组分别为73.33％(44/60)和50.00％(30/60).激素受体阴性乳腺癌组织中,AR表达与月经状态、肿瘤大小、组织学分级、EGFR表达及HER2状态相关,均P值＜0.05;在HER2过表达组中,AR表达与月经状态、淋巴结受累、EGFR表达相关,均P值＜0.05;三阴组中,AR表达与肿瘤大小和组织学分级相关,均P值＜0.05.Kaplan-Meier法分析显示,HER2过表达组中AR表达与患者的3年DFS呈正相关,P＜0.05;Cox回归法分析结果示,肿瘤大小、淋巴结受累、EGFR表达、AR表达均与患者的3年DFS有关,P＜0.05.结论 AR可能成为筛选激素受体阴性乳腺癌高危人群和预测其预后的辅助指标之一,可作为激素受体阴性乳腺癌的新治疗靶点,为不同HER2状态乳腺癌治疗提供新思路.     

Investigation of MRP-1 protein and MDR-1 P-glycoprotein expression in invasive breast cancer: a prognostic study

The efficacy of breast cancer treatment is limited by the development of resistance to various chemotherapeutic agents. We conducted a retrospective study of the expression of 2 drug resistance efflux pumps, MRP-1 and MDR-1 Pgp, in 177 invasive breast carcinomas. Immunohistochemical expression of these proteins was correlated with clinicopathologic characteristics as well as relapse-free survival (RFS) and overall survival (OS) times. MDR-1 Pgp was associated strongly with higher histologic grade (grade III). A highly significant association was shown between MDR-1 Pgp and MRP-1 expression (p < 0.01), 47.4% of patients expressing both proteins; MRP-1 was expressed in approximately 61% of patients and MDR-1, in approximately 66% of patients. No association was shown in the overall group between either MDR-1 Pgp or MRP-1 and any of the other clinicopathologic features. Kaplan-Meier analysis revealed that in a subset of patients with either high-grade (grade III) stage 1 (node-negative) or stage 2 (node-positive) tumours who were treated with surgery followed by adjuvant chemotherapy, MRP-1 expression in <25% of tumour cells at diagnosis was significantly associated with improved RFS (p < 0.02) and OS (p < 0.02). Using multivariate analysis, MRP-1 expression in <25% of tumour cells at diagnosis was identified as an independent, significant prognostic factor for RFS (p < 0.01) and OS (p < 0.01) in this patient group but not in other groups. In this subgroup, no significant correlation was observed between expression of MDR-1 Pgp and MRP-1. While the number of patients with high-grade tumours treated with adjuvant chemotherapy was small and further confirmatory research is warranted, it appears that assessment of MRP-1 expression at diagnosis may offer useful prognostic information in subgroups of patients with stage 1 or stage 2 high-grade tumours who receive CMF-based adjuvant chemotherapy. Given the known substrate specificities of MRP-1, any mechanistic relationship between MRP-1 expression and CMF resistance remains unclear. No association was shown between MDR-1 Pgp expression and either RFS or OS time in any subgroup of patients.     

鞣花酸通过下调ERK1/2抑制MCF-7乳腺癌细胞的增殖

目的:探讨鞣花酸在雌激素诱导的乳腺癌细胞增殖中的作用及细胞和分子机制。方法:雌激素培养乳腺癌细胞MCF-7,鞣花酸培养液处理,观察细胞增殖情况。采用Western blot观察细胞外调节蛋白激酶1/2（ERK1/2）的表达。结果:雌激素可明显促进MCF-7细胞增殖,与对照组比较有显著性差异,并能激活ERK1/2,使p-ERK1/2表达明显增加,且具有时间依从性。鞣花酸可明显抑制雌激素诱导的MCF-7细胞增殖,并抑制p-ERK1/2的表达,呈剂量依赖性。结论:雌激素通过激活ERK1/2诱导MCF-7细胞增殖,而这一效应可被鞣花酸抑制。     

An evaluation of lymphovascular invasion in relation to biology and prognosis according to subtypes in invasive breast cancer

Lymphovascular invasion (LVI) is associated with a poor outcome in breast cancer. The purpose of the present study was to evaluate the clinical significance of LVI in primary breast cancer and to investigate disease-free survival as a prognostic marker according to the breast cancer subtypes. This study examined 4,652 consecutive cases of invasive breast cancer excluding the patients with non-invasive cancer, stage IV and those who underwent neo-adjuvant therapy from February 2002 to February 2021. The clinicopathological characteristics and prognosis of LVI-positive and -negative tumors were compared. LVI was evaluated in H&E staining specimens from surgically resected samples. The LVI expression rates were 29.2% (low, 19.7%; high, 9.5%) in all primary cases. The LVI-positive rate was significantly associated with specimens with the following characteristics: ER/PgR-negative, HER2-positive, p53 overexpression, higher Ki-67 index values, higher nuclear grade, positive nodes and larger tumors. Moreover, the subtypes were significantly associated with LVI positivity; 20% in Luminal A, 34.6% in Luminal B, 40.9% in Lumina/HER2, 38.1% in HER2-enriched and 29.8% in triple negative (TN). There were significant differences in disease-free survival between LVI status in Luminal A, Luminal B and TN subtypes, but there was no difference in the Luminal/HER2 and HER2-enriched subtypes. A multivariate analysis revealed that LVI was a significant factor in Luminal B and TN subtypes. Overall, LVI was significantly associated with the advanced and aggressive characteristics in breast cancer. Luminal A type had a lower LVI rate, and HER2 type had a higher LVI rate. Moreover, LVI was a significant prognostic factor in Luminal B and TN subtypes. These data suggested that the LVI status was useful in predicting the prognosis in HER2 negative breast cancer cases.     

Disease-free interval and estrogen receptor activity in tumor tissue of patients with primary breast cancer: analysis after long-term follow-up

Summary Specific estrogen receptor activity (ER) was found in 115 of 175 (66%) tumors of patients treated for primary breast cancer in the period 1974–1981; 60 patients had ER-negative tumors. All patients were under observation for at least 48 months (median 76 months). The 24 patients who received adjuvant chemotherapy as part of their initial treatment, were excluded from the analysis of the disease-free interval (DFI). Groups of patients with ER-positive or ER-negative tumors did not differ significantly in clinical characteristics. Patients with ER-positive tumors had a significantly longer DFI than those with ER-negative tumors only in the first year after initial treatment. After prolonged observation a significant difference in recurrence rates was no longer found. In premenopausal women, the DFI was not different for those with ER-positive compared to those with ER-negative tumors, not even in the first year of observation. However, in postmenopausal women, those with ER-positive tumors had a significantly longer DFI up to 3 years after initial treatment but not thereafter. There was no difference in DFI between the ER-positive and ER-negative groups when the tumor stage was taken into account. It is concluded that the ER status of the primary tumor affects prognosis only on the short term.     

SERPINA1 is a direct estrogen receptor target gene and a predictor of survival in breast cancer patients

Of all breast cancer patients, about 70% are ER+ and 10% are ER+/HER2+. The ER+/HER2+ patients have a worse outcome compared to ER+/HER2- patients. Currently there is a lack of effective prognosis biomarkers for the prediction of outcome in ER+/HER2+ patients. Genome-wide differences in ER binding between the endocrine-responsive and endocrine-resistant cells were discovered using ChIP-seq, and combined with gene expression microarray data to identify direct ER target genes. These genes were correlated to survival outcome using publicly available breast cancer patient cohorts. We found the expression of the gene SERPINA1 to have a significant predictive value for the overall survival (OS) of ER+ patients in the TCGA cohort, and validated this finding in the Curtis cohort. SERPINA1 also has a significant predictive value for the OS of ER+/HER2+ patients in the TCGA cohort, with validation in the Bild cohort. The expression of SERPINA1 can be suppressed by fulvestrant and HER2 siRNA. Our results indicate that ER is constitutively activated, resulting in an E2-independent ER binding to the SERPINA1 gene and upregulation of SERPINA1 expression. Importantly, results of survival correlation suggests that high expression of SERPINA1 could be predictive for a better clinical outcome of ER+ and ER+/HER2+ patients.     

Elevated expression of syntenin in breast cancer is correlated with lymph node metastasis and poor patient survival

Introduction

Syntenin is a scaffolding-PDZ domain-containing protein. Although it is reported that syntenin is associated with melanoma growth and metastasis, the possible role of syntenin in breast cancer has not been well elucidated. The present study investigated the expression and function of syntenin in breast cancer.

Methods

Real-time polymerase chain reaction (PCR) and Western blots were used to determine the mRNA and protein expression of syntenin. With a combination of overexpression and RNA interference, the effect of syntenin on migration, invasion, and ERK1/2 activation was examined in breast cancer cell lines. The effect of syntenin in vivo was assessed with an orthotropic xenograft tumor model in BALB/c nu/nu mice. In addition, the expression level of syntenin in clinical breast cancer tissues was evaluated with immunohistochemistry. The Kaplan-Meier survival curve was used to evaluate patient survival, and the Cox proportional hazards model was used for multivariate analysis.

Results

Our study showed that syntenin expression was upregulated in high-metastasis breast cancer cell lines and breast cancer tissues. Overexpression of syntenin in breast cancer cells promoted cell migration and invasion in vitro. Moreover, overexpression of syntenin promoted breast tumor growth and lung metastasis in vivo. We further showed that activation of integrin β1 and ERK1/2 was required for syntenin-mediated migration and invasion of breast cancer cells. The correlation between syntenin expression and tumor size (P = 0.011), lymph node status (P = 0.001), and recurrence (P = 0.002) was statistically significant. More important, syntenin expression in primary tumors was significantly related to patients'' overall survival (OS; P = 0.023) and disease-free survival (DFS; P = 0.001). Its status was an independent prognostic factor of OS (P = 0.049) and DFS (P = 0.002) in our cohort of patients.

Conclusions

These results suggest that syntenin plays a significant role in breast cancer progression, and it warrants further investigation as a candidate molecular marker of breast cancer metastasis and a potential therapeutic target.     

乳腺癌组织PS2与雌激素和孕激素受体的关系及预后意义

目的 :探讨PS2在乳腺癌中的表达及其与雌激素受体 (ER)、孕激素受体 (PR)关系和预后意义。方法 :采用链亲和素(LSAB)法检测 110例乳腺癌中PS2的表达。结果 :PS2在乳腺癌组织中的阳性表达率为3 9 0 9% ( 4 3 / 110 ) ,其表达与患者年龄无关 ,P >0 0 5 ;与乳腺癌瘤体大小、腋淋巴结转移呈负相关 ,P <0 0 5。在ER阳性组和阴性组 ,PS2阳性率分别为 48 5 3 % ( 3 3 / 68)和2 3 81% ( 10 / 42 ) ,P =0 0 1;在PR阳性组和阴性组 ,PS2阳性率分别为 49 15 % ( 2 9/ 5 9)和2 7 45 % ( 14 / 5 1) ,P =0 0 2 ,PS2表达与ER、PR呈正相关关系。结论 :PS2可作为判断乳腺癌预后及预测术后抗雌激素治疗效果的重要指标     

pS2 expression in primary breast carcinomas: Relationship to clinical and histological features and survival

Summary pS2 protein expression has been reported to have prognostic significance in human breast carcinomas and to correlate with estrogen receptor positivity, although these findings have not been confirmed by all investigators. pS2 positivity was compared to various clinical and histologic parameters in a retrospective study of 290 patients (median follow-up 7.2 years) and significantly correlated with tumor grade and estrogen receptor content (p=0.001 and p=0.0007, respectively). Significant associations between pS2 positivity and lymph node metastases, T stage, histologic tumor type, and patient age were not observed. Univariate and multivariate analyses (controlling for estrogen receptor content, T and N stage) of the patient population at large showed that pS2 positivity was not predictive of disease-free or overall survival. Univariate analysis of lymph node negative patients demonstrated that both pS2 and estrogen receptor positivity were significantly associated with a better outcome. Multivariate analysis of these patients, however, showed that only estrogen receptor data had independent prognostic significance. This study suggests that immunohistochemical analysis for pS2 protein expression will not contribute additional prognostic information if the estrogen receptor content is known.