Y-box factor YB-1 predicts drug resistance and patient outcome in breast cancer independent of clinically relevant tumor biologic factors HER2, uPA and PAI-1.

Intrinsic or acquired resistance to chemotherapy is responsible for failure of current treatment regimens in breast cancer patients. The Y-box protein YB-1 regulates expression of the P-glycoprotein gene mdr1, which plays a major role in the development of a multidrug-resistant tumor phenotype. In human breast cancer, overexpression and nuclear localization of YB-1 is associated with upregulation of P-glycoprotein. In our pilot study, we analyzed the clinical relevance of YB-1 expression in breast cancer (n = 83) after a median follow-up of 61 months and compared it with tumor-biologic factors already used for clinical risk-group discrimination, i.e., HER2, urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1). High YB-1 expression in tumor tissue and surrounding benign breast epithelial cells was significantly associated with poor patient outcome. In patients who received postoperative chemotherapy, the 5-year relapse rate was 66% in patients with high YB-1 expression. In contrast, in patients with low YB-1 expressions, no relapse has been observed so far. YB-1 expression thus indicates clinical drug resistance in breast cancer. Moreover, YB-1 correlates with breast cancer aggressiveness: in patients not treated with postoperative chemotherapy, those with low YB-1 expression are still free of disease, whereas the 5-year relapse rate in those with high YB-1 was 30%. There was no significant correlation between YB-1 expression and either HER2 expression or uPA and PAI-1 levels. Risk-group assessment achieved by YB-1 differed significantly from that by HER2 or uPA/PAI-1. In conclusion, YB-1 demonstrated prognostic and predictive significance in breast cancer by identifying high-risk patients in both the presence and absence of postoperative chemotherapy, independent of tumor-biologic factors currently available for clinical decision making.     

Predictive and Prognostic Roles of Ribonucleotide Reductase M1 in Patients with Pancreatic Cancer Treated with Gemcitabine: A Meta-analysis

Increasing scientific evidence suggests that ribonucleotide reductase M1 (RRM1) may be a powerful predictorof survival in patients with pancreatic cancer treated with adjuvant gemcitabine-based chemotherapy afteroperative resection, but many existing studies have yielded inconclusive results. This meta-analysis aimedto assess the prognostic role of RRM1 in predicting survival in patients with pancreatic cancer treated withgemcitabine. An extensive literature search for relevant studies was conducted on PubMed, Embase, Web ofScience, Cochrane Library, and CBM databases from their inception through May 1st, 2013. This meta-analysiswas performed using the STATA 12.0 software and crude hazard ratios (HRs) with 95% confidence intervals(CIs) were calculated. Eight clinical studies were included in this meta-analysis with a total of 665 pancreaticcancer patients treated with adjuvant gemcitabine-based chemotherapy, including 373 patients in the high RRM1expression group and 292 patients in the low RRM1 expression group. Our meta-analysis revealed that highRRM1 expression was associated with improved overall survival (OS) of pancreatic cancer patients (HR=1.56,95%CI=0.95-2.17, P<0.001). High RRM1 expression also was linked to longer disease-free survival (DFS) thanlow RRM1 expression (HR=1.37, 95%CI=0.25-2.48, P=0.016). In conclusion, our meta-analysis suggests thathigh RRM1 expression may be associated with improved OS and DFS of pancreatic cancer patients treated withadjuvant gemcitabine-based chemotherapy. Detection of RRM1 expression may be a promising biomarker forgemcitabine response and prognosis in pancreatic cancer patients.     

Expression of HER2 and estrogen receptor alpha depends upon nuclear localization of Y-box binding protein-1 in human breast cancers

In our present study, we examined whether nuclear localization of Y-box binding protein-1 (YB-1) is associated with the expression of epidermal growth factor receptors (EGFR), hormone receptors, and other molecules affecting breast cancer prognosis. The expression of nuclear YB-1, clinicopathologic findings, and molecular markers [EGFR, HER2, estrogen receptor (ER)alpha, ER beta, progesterone receptor, chemokine (C-X-C motif) receptor 4 (CXCR4), phosphorylated Akt, and major vault protein/lung resistance protein] were immunohistochemically analyzed. The association of the expression of nuclear YB-1 and the molecular markers was examined in breast cancer cell lines using microarrays, quantitative real-time PCR, and Western blot analyses. Knockdown of YB-1 with siRNA significantly reduced EGFR, HER2, and ER alpha expression in ER alpha-positive, but not ER alpha-negative, breast cancer cell lines. Nuclear YB-1 expression was positively correlated with HER2 (P = 0.0153) and negatively correlated with ER alpha (P = 0.0122) and CXCR4 (P = 0.0166) in human breast cancer clinical specimens but was not correlated with EGFR expression. Nuclear YB-1 expression was an independent prognostic factor for overall (P = 0.0139) and progression-free (P = 0.0280) survival. In conclusion, nuclear YB-1 expression might be essential for the acquisition of malignant characteristics via HER2-Akt-dependent pathways in breast cancer patients. The nuclear localization of YB-1 could be an important therapeutic target against not only multidrug resistance but also tumor growth dependent on HER2 and ER alpha.     

Expression of drug resistance proteins in breast cancer,in relation to chemotherapy

Drug resistance plays an important role in chemotherapy failure in breast cancer. We studied the expression of MDR1, MRP, LRP, DNA topoisomerases, p53 and Ki-67 in different groups of breast cancer patients in relation to chemotherapy. Tissues from 6 normal breasts and 20 primary operable, 40 locally advanced and 10 anthracycline-resistant metastatic breast cancers were assessed. Sequential samples of the same patient were available from 17 patients with locally advanced breast cancer undergoing neo-adjuvant chemotherapy and in 7 metastatic patients undergoing paclitaxel treatment. Protein expression was investigated by immunohistochemistry. Significantly higher protein expression was observed for Pgp, Ki-67 and p53 in the locally advanced breast cancers than in primary operable breast cancers. No other significant differences in protein expression were found among the 3 breast cancer groups. Expression of none of the markers that could be assessed (Pgp, MRP, LRP, p53 and Ki-67) in locally advanced breast cancer had predictive value for pathological response. Interestingly, after chemotherapy a significant decrease in percentage of Ki-67 positive tumor cells was observed, whereas the other markers did not vary substantially. Furthermore, considering all breast cancer samples, a cumulative dose of doxorubicin >400 mg/m² inversely correlated with Ki-67 positivity. However, 2 patients with a pathological complete remission had only 5-10% Ki67-positive tumor cells before chemotherapy, indicating that Ki67 negativity itself is not responsible for chemoresistance. In conclusion, none of the known proteins related to multidrug resistance predicted response to chemotherapy in breast cancer, and resistant clones left behind generally had a low proliferation rate.Int. J. Cancer 71: 787-795, 1997. © 1997 Wiley-Liss Inc.     

Prognostic significance of basal-like phenotype and fascin expression in node-negative invasive breast carcinomas.

PURPOSE: Basal-like phenotype tumors are frequently found among BRCA1 germ-line mutated breast carcinomas. They are biologically aggressive and have a tendency towards visceral metastasis when untreated. Nevertheless, it has been suggested that they respond to chemotherapy better than other types of tumors. Fascin expression has been associated with lung metastasis in breast cancer. The aim of this study was to determine whether basal-like phenotype and fascin were related in both sporadic and familial tumors and with prognosis in node-negative sporadic breast cancers. EXPERIMENTAL DESIGN: 230 nonfamilial and 28 hereditary node-negative invasive breast carcinomas were immunohistochemically analyzed using tissue microarrays. Tumors that were estrogen receptor/HER2 negative and cytokeratin 5/6 and/or epidermal growth factor receptor positive were considered to have a basal-like phenotype. RESULTS: A basal-like phenotype was found in 11.9% of sporadic cancers. Among patients not receiving adjuvant chemotherapy, a basal-like phenotype was associated with poor prognosis (P = 0.001, log-rank test) whereas no such association was found in patients receiving it. Tumors with a basal-like phenotype showed local recurrence (17.4%) or visceral metastasis (13%) but not bone metastasis (P = 0.001). Fascin expression was observed in 25.1% of sporadic invasive breast carcinomas and was associated with the basal-like phenotype, but not with prognosis or recurrence pattern. Fascin was expressed in 83.3% and 16.7% BRCA1- and BRCA2-associated carcinomas, respectively (P = 0.048). CONCLUSIONS: Basal-like tumors had a tendency towards visceral metastasis and their prognosis was dependent on the use of postoperative chemotherapy. Although fascin expression was associated with the basal-like phenotype, it was not associated with their metastatic behavior. Fascin expression is frequent in BRCA1-associated tumors.     

YB-1在青年型乳腺癌组织中的表达及意义

目的:探讨YB-1(Y-box binding protein 1)在青年型乳腺癌组织中的表达及意义。方法:应用免疫组织化学方法研究YB-1蛋白在青年型乳腺癌组织中的表达,并结合病理组织学类型、病理分级等临床特征分析YB-1在青年型乳腺癌组织中的表达意义;依据ER、PR、HER-2、CK5/6表达对青年型乳腺癌进行分子分型(Luminal-A、Luminal-B、HER2+和Basal-like 4个分子亚型),并分析其与YB-1表达的关系。结果:HE结果显示64例青年型乳腺癌病理组织学分类主要为浸润性导管癌,占59.4%。免疫组化结果显示64例青年型乳腺癌组织中YB-1阳性率为92.2%,其中细胞核阳性表达率53.1%,细胞浆阳性表达率39.1%。肿瘤>2cm的患者占59.4%,YB-1主要表达在细胞核(40.6%),患者肿瘤?2cm占37.5%,YB-1则主要在细胞浆表达(20.3%),YB-1表达类型与肿瘤大小有显著统计学意义(P=0.036)。组织学3级所占比例最高,占48.4%,且多为YB-1细胞核表达(37.5%),乳腺癌不同的组织学分级间YB-1的表达率不同(P=0.000);青年型乳腺癌患者发生淋巴结转移的比例高(84.4%),其中N3期所占比例最高,占40.6%,YB-1主要在细胞核表达,占31.3%,胞浆表达占7.8%。青年型乳腺癌分子分型中主最多见的是Luminal-B型,占46.9%,YB-1主要表达在细胞核(32.8%),浆表达仅占9.4%,统计分析显示YB-1表达的核浆分布特点与青年型乳腺癌分子分型有关(P=0.04)。结论:YB-1在青年型乳腺癌组织中的表达特点与肿瘤大小、病理组织分级及淋巴结状态有一定关系,细胞核阳性主要见于肿瘤>2cm的患者,而细胞浆阳性主要见于肿瘤?2cm的患者,且YB-1细胞核表达主要为组织学3级,且青年型乳腺癌淋巴结转移率高,YB-1主要在细胞核表达;青年型乳腺癌不同分子分型中YB-1蛋白表达存在差异,YB-1可能成为青年型乳腺癌防治的新的分子靶点。     

Microtubule-associated protein-tau is a bifunctional predictor of endocrine sensitivity and chemotherapy resistance in estrogen receptor-positive breast cancer.

PURPOSE: The clinical outcome for patients with breast cancer is influenced by the metastatic competence of the cancer and its sensitivity to endocrine therapy and chemotherapy. A molecular marker may be prognostic of outcome or predictive of response to therapy, or a combination of both. EXPERIMENTAL DESIGN: We examined separately the prognostic and predictive values of tau mRNA expression in estrogen receptor (ER)-positive primary breast cancers in three patient cohorts. We used gene expression data from 209 untreated patients to assess the pure prognostic value of tau, data from 267 patients treated with adjuvant tamoxifen to assess predictive value for endocrine therapy, and data from 82 patients treated with preoperative paclitaxel followed by 5-fluorouracil, doxorubicin, and cyclophosphamide (paclitaxel/FAC) to assess predictive value for chemotherapy response. Wilcoxon rank sum test was used to compare tau expression between different outcome groups. RESULTS: Higher tau mRNA expression showed borderline nonsignificant association with better prognosis in the absence of systemic adjuvant therapy. Higher tau mRNA expression was significantly associated with no recurrence (at 5 and 10 years, P = 0.005 and P = 0.05, respectively) in patients treated with tamoxifen, indicating a predictive value for endocrine therapy. Tau expression was significantly lower in patients who achieved pathologic complete response to paclitaxel/FAC chemotherapy (P < 0.001). CONCLUSION: This study suggests that high tau mRNA expression in ER-positive breast cancer indicates an endocrine-sensitive but chemotherapy-resistant disease. In contrast, low tau expression identifies a subset of ER-positive cancers that have poor prognosis with tamoxifen alone and may benefit from taxane-containing chemotherapy.     

联合检测 ERCC1、BRCA1、RRM1表达在非小细胞肺癌选择化疗方案中的意义

目的：探讨检测非小细胞肺癌组织中 ERCC1、BRCA1、RRM1的蛋白表达在化疗方案选择中的临床意义。方法：选取确诊非小细胞肺癌患者120例,随机分为两组。常规化疗组（60例）给予吉西他滨／紫杉醇＋顺铂化疗;实验组（60例）：化疗前检测 ERCC1、RRM1、BRCA1蛋白的表达,选用敏感的化疗药物治疗。比较两组的疗效、无疾病进展时间和生存期。结果：实验组中 ERCC 1蛋 白 和 BRCA 1蛋 白 表 达 阳 性 率 为28．33％,RRM1蛋白表达阳性率为51．67％。治疗两周期后评价常规化疗组和实验组的化疗客观缓解率分别是35．00％（21／60）,43．33％（26／60）,无统计学差异（P ＞0．05）。两组无疾病进展平均时间、中位时间分别为实验组6．653个月、4．8个月;常规化疗组4．35个月、3．5个月,有统计学意义（P ＜0．05）。生存分析两组比较差异无统计学意义（P ＞0．05）。结论：检测 ERCC1蛋白、BRCA1蛋白、RRM1蛋白的表达选择化疗方案使非小细胞肺癌患者在临床化疗中获益,可以延长无疾病进展时间。     

P-Glycoprotein and multidrug resistance-related protein expressions in relation to technetium-99m methoxyisobutylisonitrile scintimammography findings

The purpose of this study was to retrospectively study 48 patients with infiltrating ductal breast cancer to evaluate the relationship between the degree of accumulation of technetium-99m methoxyisobutylisonitrile (Tc-MIBI) and P-glycoprotein (Pgp) or multidrug resistance-related protein (MRP) expression in breast cancer tissues. Before surgery or biopsy, all 48 patients underwent scintimammography started 10 min after the injection of Tc-MIBI. Tumor:background (T:B) ratios were calculated from the Tc-MIBI scintimammography. Immunohistochemical analysis was performed on the pathological specimens of the 48 breast tumors to determine Pgp and MRP expression. According to the results of immunohistochemical analysis, the 48 breast cancers were separated into four groups: (a) group 1, 12 cancers with both positive Pgp expression and positive MRP expression; (b) group 2, 12 cancers with positive Pgp expression and negative MRP expression; (c) group 3, 12 cancers with negative Pgp expression and positive MRP expression; and (d) group 4, 12 cancers with both negative Pgp expression and negative MRP expression. Among the four groups, the T:B ratio was lowest in group 1 (1.13+/-0.10) and highest in group 4 (2.17+/-0.14), respectively (P < 0.05). The T:B ratios of groups 2 (1.30+/-0.25) and 3 (1.32+/-0.26) were between those of groups 1 and 4. Our data confirmed that Tc-MIBI scintimammography is useful for determining Pgp and MRP expression in patients with breast cancers.     

P7 antigen expression in human breast cancer.

PURPOSE: Evaluate p7 expression in human breast cancer and determine whether chemotherapy and radiation therapy effect a change in p7 expression. EXPERIMENTAL DESIGN: Using a p7-specific monoclonal antibody with immunohistochemistry and Western immunoblot analyses to assess p7 expression in archival, frozen breast cancer specimens both before and after therapy. RESULTS: A novel 7 kDa protein (p7), originally identified in multidrug-resistant ovarian and breast cancer cell lines, was found to be expressed in 21 of 64 (32%) primary, unselected human breast cancer specimens by immunohistochemistry with the use of a p7-specific monoclonal antibody, 1D7. P7 was observed in malignant cells but not in other types of cells in the breast tissue. Western blot analysis confirmed the 7 kDa polypeptide in p7-positive breast carcinomas identified by immunohistochemistry. P7 expression was significantly associated with breast cancers having distant metastasis and/or local recurrence (P = 0.027, Fisher's exact test). In addition, p7 expression was significantly increased in post-treatment breast cancer biopsy specimens compared with pretreatment breast cancer biopsy specimens in patients with locally advanced breast cancer after 5-fluorouracil chemotherapy and radiation therapy [2 of 15 (13%) pretreatment breast cancers compared with 8 of 15 (53%) post-treatment breast cancers; P = 0.016, McNemar's test]. CONCLUSIONS: These findings demonstrate that expression of p7 is associated with malignant tumor cells in primary breast cancers, especially those showing recurrent or metastatic disease. Its specific association with the malignant phenotype suggests it may have potential for novel target-based therapies. The markedly increased expression in patients with locally advanced disease after neoadjuvant therapy suggests a role for p7 in treatment outcome.     

Ribonucleotide reductase M1 gene promoter activity, polymorphisms, population frequencies, and clinical relevance

RRM1 is a gene crucial for determination of the tumor phenotype. It encodes the regulatory subunit of ribonucleotide reductase, and it is a molecular target of gemcitabine. In addition, RRM1 induces PTEN expression and inhibits cell migration, invasion, and metastasis formation. In patients with resected lung cancers, increased levels of RRM1 are highly associated with long survival. In contrast, patients on gemcitabine and cisplatin therapy for advanced disease have a poor survival if RRM1 expression is high presumably because of decreased efficacy of chemotherapy. We analyzed the RRM1 promoter for polymorphisms in an effort to develop a practical and inexpensive assay for RRM1 expression. Two single nucleotide polymorphisms, RR37 and RR524, were discovered. These polymorphisms impacted promoter activity in vitro and had different frequencies in various populations. Promoter allelotypes were highly associated with overall (P = 0.06) and disease-free (P = 0.03) patient survival. The allelotype with the highest predicted activity was associated with the best patient outcome. However, we did not find an association between allelotype and tumoral RRM1 expression. This is likely a result of the limited impact of the described promoter polymorphisms on overall in vivo gene expression. We conclude that clinical studies using RR37 and RR524 for decisions on chemotherapy are premature and that further functional studies on the RRM1 promoter are required to fully elucidate factors controlling RRM1 expression.     

Efficacy of adjuvant chemotherapy according to Prion protein expression in patients with estrogen receptor-negative breast cancer.

BACKGROUND: Prion protein (PrPc) has been previously reported to be associated with resistance to proapoptotic stimuli. We evaluated whether the expression of PrPc was associated with the resistance to adjuvant chemotherapy in patients with estrogen receptor (ER) -negative breast cancer. PATIENTS AND METHODS: The expression of PrPc by primary tumors was assessed by immunohistochemistry in a series of 756 patients included in two randomized trials that compared anthracycline-based chemotherapy to no chemotherapy. The PrPc expression was correlated with ER expression and the benefit of adjuvant chemotherapy was assessed according to PrPc expression in patients with ER-negative tumors. RESULTS: Immunostaining analysis showed that PrPc was mainly expressed by myoepithelial cells in normal breast tissue. Tissue microarray analysis from 756 breast tumors showed that PrPc was associated with ER-negative breast cancer subsets (P < 0.001). Adjuvant chemotherapy was not associated with a significant risk reduction for death in patients with ER-negative/PrPc-positive disease [adjusted hazard ratio (HR) for death = 0.98, 95% confidence interval (CI) 0.45-2.1, P = 0.95], while it decreased the risk for death (HR = 0.39, 95% CI 0.2-0.74, P = 0.004) in patients with ER-negative/PrPc-negative tumors. CONCLUSION: These data indicate that ER-negative/PrPc-negative phenotype is associated with a high sensitivity to adjuvant chemotherapy.     

非小细胞肺癌组织ERCC1和RRM1基因表达及其对预后影响探讨

目的比较非小细胞肺癌（non-small cell lung cancer,NSCLC）患者原发灶与转移淋巴结中切除修复交叉互补基因1（excision repair cross-complementation group1,ERCC1）和核糖核苷酸还原酶M1亚基（ribonucleotidereductase subunit M1,RRM1）表达情况,探讨ERCC1和RRM1表达状态与NSCLC患者治疗效果及预后的关系,为NSCLC患者的合理治疗提供依据。方法选取山东省肿瘤医院外科六病区2008-08-01-2012-08-31行手术切除且术后病理确诊为NSCLCⅡA-ⅢA期的患者106例,所有患者术前均未接受任何针对肿瘤的治疗措施,均釆用免疫组化技术测定组织中ERCC1和RRM1表达状况,术后均采用长春瑞滨联合顺铂（NP方案）进行辅助化疗,并进行临床随访。结果 NSCLC癌组织及转移淋巴结中RRM1阴性表达患者中位无疾病进展时间分别为23.1和24.7个月,显著优于RRM1阳性表达患者的16.4和19.1个月,两组比较差异有统计学意义,P值分别为0.007和0.026;而ERCC1阴性表达患者中位无疾病生存期为17.5个月,与ERCC1阳性表达患者的19.4个月比较,差异无统计学意义,P=0.59。原发灶和淋巴结转移灶中ERCC1和RRM1的表达水平差异无统计学意义,P〉0.05。不同性别、分期及病理类型的NSCLC患者ERCC1及RRM1表达水平差异均无统计学意义,P〉0.05。结论 NSCLC患者癌组织及转移淋巴结中,RRM1基因表达情况可作为NP方案术后辅助化疗预后的重要指标。     

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.     

Alteration of Y-box binding protein-1 expression modifies the response to endocrine therapy in estrogen receptor-positive breast cancer

Y-box binding protein-1 (YB-1) plays an important role in tumor progression and drug resistance. This study examined whether YB-1 is involved in the alteration of response to endocrine therapy in estrogen receptor (ER)-positive breast cancer cells. MCF7 cells that stably expressed YB-1 (MCF7-YB-1) and vector control cells (MCF7-vector) were established. These cells were used to analyze the expression of the factors related to ER and growth factor receptor signaling pathways and responses to antiestrogens (tamoxifen and fulvestrant) and estrogen responsive element (ERE) activity. The effect of knocking down endogenous YB-1 expression was tested in wild-type MCF7 cells. In addition, the expression of YB-1 and the factors related to ER and growth factor receptor signaling pathways were evaluated in clinical breast cancers treated with preoperative chemotherapy. The expression of HER2, AIB1, p-Erk, and c-Myc was increased in MCF7-YB-1 cells. In contrast, knocking down of YB-1 decreased the expression of these factors but increased the expression of ERα in wild-type MCF7 cells. Furthermore, sensitivity to antiestrogens was decreased in the MCF7-YB-1 in comparison to that in MCF7-vector cells. The introduction of YB-1 into MCF7 cells inhibited apoptosis and cell cycle arrest at G1 phase induced by antiestrogens. In MCF7-YB-1 cells, the expression levels of p-Erk and c-Myc were continuously upregulated when cells were treated with either tamoxifen or fulvestrant. The ERE activity was reduced in MCF7-YB-1 cells in comparison to MCF7-vector cells, and the ERE activity in MCF7-YB-1 cells was inhibited by fulvestrant at a lower concentration than that which inhibited the ERE activity in MCF7-vector cells. In ER-positive clinical breast cancers treated with preoperative chemotherapy, significantly more number of specimens that showed increased or positive YB-1 expression after chemotherapy was positive for HER2 expression. These data suggest that alteration of YB-1 may modify the crosstalk between the ER pathway and HER2 pathway in ER-positive breast cancer cells, and consequently, may alter the response to endocrine therapy in ER-positive breast cancer cells.     

GRP78 as potential predictor for breast cancer response to adjuvant taxane therapy

Few predictive markers exist for response to adjuvant chemotherapy in breast cancer. The 78‐kDa glucose‐regulated protein (GRP78) is a potent antiapoptotic factor, conferring drug resistance. Recently, we reported that high GRP78 expression in breast cancer specimens predicts a shorter recurrence‐free survival in patients who received doxorubicin‐based adjuvant chemotherapy. Interestingly, the opposite effect was observed in 25 patients who additionally received a taxane. To confirm this potentially paradigm shifting finding, we investigated whether GRP78 is associated with recurrence‐free survival in an independent cohort of taxane‐treated breast cancer patients. Immunohistochemical staining of GRP78 was performed on archival paraffin‐embedded formalin‐fixed tumor specimens obtained from 48 female breast cancer patients before chemotherapy treatment. These patients received doxorubicin and cyclophosphamide, followed by paclitaxel or docetaxel on a clinical trial. GRP78 expression level was evaluated by a pathologist, masked to all clinical and outcome data. Association between GRP78 expression and recurrence‐free survival was evaluated. GRP78 positivity predicts a better recurrence‐free survival, independent of other prognostic factors [hazard ratio (HR) for moderate positivity: 0.40 (95% confidence interval (CI): 0.087–1.83); HR for strong positivity: 0.16 (95% CI: 0.018–1.50); p_trend = 0.053]. In a pooled analysis with the previous 25 patients, almost identical HRs were obtained with p_trend = 0.024. This provides further evidence that GRP78 is a potential independent predictor for response to taxane‐based adjuvant chemotherapy in breast cancer.     

Expression of RRM1 and its association with resistancy to gemcitabine-based chemotherapy in advanced nasopharyngeal carcinoma

Gemcitabine has high activity against nasopharyngeal carcinoma(NPC).The level of ribonucleotide reductase subunit M1(RRM1) expression is closely related to the efficacy of gemcitabine on non-small cell lung cancer and pancreatic cancer.However,the expression of RRM1 and its association with sensitivity to gemcitabine-based chemotherapy in advanced NPC is not known.In this study,we retrospectively collected 48 formalin-fixed,paraffin-embedded NPC tissues to evaluate the expression of RRM1 using immunohistochemistry.All patients were diagnosed and treated with gemcitabine-based chemotherapy at Sun Yat-sen University Cancer Center.RRM1 expression was positive in 17(35%) patients.RRM1 expression was not associated with sex,age,performance status,WHO histological type,number of distant metastases,previous treatment,or cycles of gemcitabine-based chemotherapy(P> 0.05).The progression-free survival of the RRM1-positive group was shorter than that of the RRM1-negative group(5 months vs.7 months,P = 0.036),and the response rate of the RRM1-positive group was somewhat lower than that of the RRM1-negative group(51.6% vs.35.3%,P = 0.278).There was no significant difference in median survival between the RRM1-positive and RRM1-negative groups(22 months vs.19 months,P = 0.540).Our results show that RRM1-negative expression is related with longer progression-free survival in advanced NPC patients treated with gemcitabine-based regimens.     

Intact Mre11/Rad50/Nbs1 complex predicts good response to radiotherapy in early breast cancer

PURPOSE: To investigate the expression and predictive role of the Mre11/Rad50/Nbs1 (MRN) complex and the ataxia-telangiectasia mutated protein (ATM) for the outcome of radiotherapy in breast cancer patients. METHODS AND MATERIALS: The protein expression of ATM and the DNA repair proteins in the MRN complex were investigated using immunohistochemistry in tumors from 224 women with early breast cancer, who were randomized to receive postoperative radiotherapy or adjuvant chemotherapy. RESULTS: Compared with normal breast tissue, the staining intensity of Mre11, Rad50, Nbs1, and ATM was reduced in a majority of the tumors. Weak expression of the MRN complex was correlated with high histologic grade and estrogen receptor negativity (p = 0.01 and p = 0.0001, respectively). Radiotherapy significantly reduced the risk of local recurrence as compared with chemotherapy (p = 0.04). The greatest benefit of radiotherapy was seen in patients with moderate/strong expression of the MRN complex (relative risk = 0.27, 95% confidence interval = 0.098-0.72, p = 0.009), whereas patients with negative/weak MRN expression had no benefit of radiotherapy compared with adjuvant chemotherapy. These results suggest that an intact MRN complex is important for the tumor cell eradicating effect of radiotherapy. CONCLUSIONS: Reduced expression of the MRN complex predicts a poor effect of radiotherapy in patients with early breast cancer.