Estrogen receptor alpha(ERα/ESR1)is overexpressed in over half of all breast cancers and is considered a valuable therapeutic target in ERαpositive breast cancer.Here,we designed a membrane-permeant Chaperonemediate...Estrogen receptor alpha(ERα/ESR1)is overexpressed in over half of all breast cancers and is considered a valuable therapeutic target in ERαpositive breast cancer.Here,we designed a membrane-permeant Chaperonemediated Autophagy Targeting Chimeras(CMATAC)peptide to knockdown endogenous ERαprotein through chaperone-mediated autophagy.The peptide contains a cell membrane-penetrating peptide(TAT)that allows the peptide to by-pass the plasma membrane,anαI peptide as a protein-binding peptide(PBD)that binds specifically to ERα,and CMA-targeting peptide(CTM)that targeting chaperone-mediated autophagy.We validated that ERαtargeting peptide was able to target and degrade ERαto reduce the viability of ERαpositive breast cancer cells.Taken together,our studies provided a new method to reduce the level of intracellular ERαprotein via CMATAC,and thus may provide a new strategy for the treatment of ERαpositive breast cancer.展开更多
The estrogen signaling system is a crucial regulator of metabolicandphysiologicalprocesses.However,abnormal activation of estrogen signaling may play a role in breast cancer initiation and progression.Crucial to this ...The estrogen signaling system is a crucial regulator of metabolicandphysiologicalprocesses.However,abnormal activation of estrogen signaling may play a role in breast cancer initiation and progression.Crucial to this pathway is the interaction between estrogen receptor alpha(ERa)and various co-transcription activators.1 Although numerous studies have investigated ER coregulators,the protein-protein interaction networks of ERa are not fully understood.Recent research has shown that high chromodomain helicase DNA-binding 4(CHD4)expression is linked to poor prognosis in various cancers.2,?In this study,we demonstrated that both CHD4 and ERαcontribute to breast cancer progression while providing evidence of the regulatory processes and functional interplay between these two proteins.展开更多
Estrogen receptor(ER) is a vital biomarker in the development and development of breast cancer, and its status has great clinical value in clinical treatment strategy, endocrine therapy efficacy prediction, and breast...Estrogen receptor(ER) is a vital biomarker in the development and development of breast cancer, and its status has great clinical value in clinical treatment strategy, endocrine therapy efficacy prediction, and breast cancer prognosis. By specifically combining <sup>18</sup>F-FES with ER, <sup>18</sup>F-FES PET/CT imaging uses standard uptake value(SUV) to semi-quantitatively reflect the distribution of ER and its biological activity in patients, and assesses the expression of ER in breast cancer patients about primary and metastases before or after treatment, to provide a basis for personalized treatment of breast cancer. In this review, we will review the imaging principles of a new ER detection method <sup>18</sup>F-FES PET/CT, and the research progress in the clinical application of breast cancer, and compare its diagnostic and treatment value with non-specific tumor imaging <sup>18</sup>F-FDG PET/CT in breast cancer.展开更多
Endoplasmic reticulum(ER)stress,as an emerging hallmark feature of cancer,has a considerable impact on cell proliferation,metastasis,invasion,and chemotherapy resistance.Ovarian cancer(OvCa)is one of the leading cause...Endoplasmic reticulum(ER)stress,as an emerging hallmark feature of cancer,has a considerable impact on cell proliferation,metastasis,invasion,and chemotherapy resistance.Ovarian cancer(OvCa)is one of the leading causes of cancer-related mortality across the world due to the late stage of disease at diagnosis.Studies have explored the influence of ER stress on OvCa in recent years,while the predictive role of ER stress-related genes in OvCa prognosis remains unexplored.Here,we enrolled 552 cases of ER stress-related genes involved in OvCa from The Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)cohorts for the screening of prognosis-related genes.The least absolute shrinkage and selection operator(LASSO)regression was applied to establish an ER stress-related risk signature based on the TCGA cohort.A seven-gene signature revealed a favorable predictive efficacy for the TCGA,International Cancer Genome Consortium(ICGC),and another GEO cohort(P<0.001,P<0.001,and P=0.04,respectively).Moreover,functional annotation indicated that this signature was enriched in cellular response and senescence,cytokines interaction,as well as multiple immune-associated terms.The immune infiltration profiles further delineated an immunologic unresponsive status in the high-risk group.In conclusion,ER stress-related genes are vital factors predicting the prognosis of OvCa,and possess great application potential in the clinic.展开更多
Objective: To study the relationship between theexpression of PS, protein and Estrogen (ER) andProgesterone Receptor (PR) status and their prognoticvalue in breast canceL Methods: Using theimmunohistochemical method, ...Objective: To study the relationship between theexpression of PS, protein and Estrogen (ER) andProgesterone Receptor (PR) status and their prognoticvalue in breast canceL Methods: Using theimmunohistochemical method, PS2 protein expressionswere detected in 105 cases with breast cancer. Results:The positive rate of PS2 protein was 50.48% (53/105) in105 cases. The positive rate of PS, in the patients whosurvived five years or more was 56.96% (45/79), whichwas higher than that of those who lived less than fiveyears (30.77%, 8/26). In the ER, PR (+) patients, thepositive rate of PS, was higher (76.74%, 33/34), thanthat of those with ER, PR (-) (22.5%, 9/40). Conclusions:Our results suggest that the expression of PS, proteinwas positively correlated with the 5-year-survival andthat of ER and PR in breast cancer. It is considered thatPS, may be as a prognostic predictor, and detection ofPS, protein expression was useful for a guidingtreatment of breast cancer.展开更多
他莫昔芬(tamoxifen,TAM)作为雌激素受体阳性(estrogen receptor,ER+)乳腺癌的一线化疗药物使大多数患者受益,但原发性和继发性耐药问题严重影响临床治疗效果。深入研究ER+乳腺癌TAM耐药机制,改善治疗效果是当前亟待解决的问题。抑癌因...他莫昔芬(tamoxifen,TAM)作为雌激素受体阳性(estrogen receptor,ER+)乳腺癌的一线化疗药物使大多数患者受益,但原发性和继发性耐药问题严重影响临床治疗效果。深入研究ER+乳腺癌TAM耐药机制,改善治疗效果是当前亟待解决的问题。抑癌因子NDRG2(N-myc downstream regulated gene 2,NDRG2)在肿瘤发生发展中发挥重要作用,但是否参与ER+乳腺癌TAM耐药尚不清楚。本研究旨在探明NDRG2在ER+乳腺癌TAM耐药中发挥的作用和机制。通过RT-PCR与免疫印迹分析对比TAM敏感型和耐药型ER+乳腺癌细胞发现,NDRG 2的mRNA转录水平和蛋白质翻译水平在TAM耐药细胞中表达显著下调,且与耐药能力负相关(P<0.001);CCK-8细胞毒性实验和软琼脂克隆形成实验证实,在耐药细胞中过表达NDRG2可显著降低TAM药物半抑制浓度IC 50和软琼脂克隆形成率(P<0.001),逆转耐药表型。分子机制上,X-box结合蛋白1(X-box binding protein 1,XBP1)mRNA剪切实验与内质网相关降解(endoplasmic-reticulum associated degradation,ERAD)报告蛋白的结果显示,过表达NDRG2可增强耐药细胞中剪切型XBP1s mRNA转录与ERAD报告蛋白CD3ε-YFP表达(P<0.001),引发耐药细胞内质网强应激反应;免疫印迹检测结果显示,过表达NDRG2可显著提高耐药细胞中内质网应激感受器肌醇需要激酶1α(inositol requiring enzyme 1,IRE1α)的磷酸化水平及其下游因子,例如内质网EIP辅助因子(endoplasmic reticulum-localized DnaJ 4,ERdj4)、PKR蛋白激酶的细胞抑制剂(cellular Inhibitor of the PKR protein kinase,P58 IPK)、α甘露糖苷酶样应激蛋白(er degradation enhancingαmannosidase likeprotein,EDEM)和蛋白质二硫键异构酶家族A成员5(protein disulfide isomerase family a member 5,PDIA5)的表达水平(P<0.001)。小鼠异种移植瘤研究进一步证实,在耐药细胞中过表达NDRG2可增强TAM治疗效果,显著抑制耐药移植瘤生长(P<0.001)。以上研究结果表明,通过提高耐药细胞中NDRG2表达,增强TAM治疗引发的内质网强烈应激,可逆转ER+乳腺癌细胞耐药性,改善TAM治疗效果。研究结果为解决ER+乳腺癌TAM耐药问题提供了新的思路和有价值的潜在药物靶点。展开更多
Aim Breast cancer is one of the lethal gynecological malignancy in the world. Tamoxifen (TAM) and fulvestrant (FUL) are the major drugs for patients with estrogen receptor-positive (ER + ) breast cancers. Howev...Aim Breast cancer is one of the lethal gynecological malignancy in the world. Tamoxifen (TAM) and fulvestrant (FUL) are the major drugs for patients with estrogen receptor-positive (ER + ) breast cancers. Howev- er, the development of endocrine resistance is the impediment for successful treatment. In this study, we explored the mechanisms of endocrine resistance and therapeutic strategy for overcoming resistance against TAM and FUL. Methods The experiments were performed in Ell + and estrogen/TAM-sensitive MCF7 cells and antiestrogen-re- sistant MCF7/LCC9 cells. Western blot and confocal microscopy were used to determine cell autophagy. Cell trans- fection and luciferase activity assay were performed to identify the target gene of miR-214. Results It showed that 4-OHT/FUL treatment induced apoptosis as well as autophagy in breast cancer cells. The increase of autophagy might be the major cause of endocrine resistance to 4-OHT or FUL. Mill-214 increased the sensitivity of breast cancer cells to the 4-OHT/FUL-induced apoptosis through inhibition of autophagy. Importantly, a negative correla- tion was established between miR-214 and UCP2 in human breast cancer tissue specimens by RT-qPCR assay. UCP2 was identified to be a direct target of mill-214. Further study in MCF7/LCC9 cells indicated that endocrine resistance might arise from activation of the PI3 K-Akt-mTOll pathway, thereby inducing autophagy by overexpres- sion of UCP2. Conclusions MiR-214 increased the sensitivity of breast cancer cells to TAM and FUL through in- hibition of autophagy by targeting UCP2. Mill-214 shows potential as a novel therapeutic strategy for overcoming endocrine resistance in ER + breast cancers.展开更多
Objective: To investigate whether dietary daidzein interact with endogenous 17β-Estradiol (E2) to give rise to additive or inhibitory effects on proliferation and apoptosis in breast cancer cells. Methods: Cell ...Objective: To investigate whether dietary daidzein interact with endogenous 17β-Estradiol (E2) to give rise to additive or inhibitory effects on proliferation and apoptosis in breast cancer cells. Methods: Cell cycle distribution and apoptosis induction were analyzed by using flow cytometry when breast cancer cell lines MCF-7 were cotreated with daidzein (1, 5 μmol/L) and E2 (0.1-10 nmol/L) for 5 days. Whether daidzein could alter E2-modulated mRNA expression of estrogen receptor alpha (ERα), estrogen receptor beta (ERI3) and ERβ-estrogen response element (ERE) dependent transcription was investigated by RT-PCR and luciferase induction assays. The effects of daidzein on E2-modulated expression of proapoptotic p53, bax and antiapoptotic bcl-2 at both mRNA and protein levels were also investigated by RT-PCR and Western blot. Results: Daidzein enhanced the antiapoptotic effect in an Ea dose-dependent manner, but had no effect on E2-induced proliferation. Daidzein antagonized E2-induced ERβ mRNA expression and ERβ-ERE dependent transcription. In addition, daidzein only antagonized E2-upregulated expression of p53 and bax, but had no effect on E2-upregulated expression of bcl-2. Conclusion: Daidzein enhances the antiapoptotic effect of E2 on breast cancer cells by inhibiting E2-mediated p53-bax proapoptotic pathway. These results suggest that dietary daidzein may enhance deleterious effect of endogenous E2 in hormone-dependent breast cancer.展开更多
Objective: hER-α36 is a variant of estrogen receptor-a, identified and cloned by a team of American. This research is to determine whether hER-α36 can enhance or weaken chemosensitivity to docetaxel in breast cance...Objective: hER-α36 is a variant of estrogen receptor-a, identified and cloned by a team of American. This research is to determine whether hER-α36 can enhance or weaken chemosensitivity to docetaxel in breast cancer cell line MCF-7(ERα66 positive). Methods: RT-PCR was used to detect the expressions of ERα66 and ERa36 in the two human breast cancer cell lines MCF-7(MCF-7/ERα66) and MCF-7 transfected with ERa36(MCF-7/ERα36). The two cell lines were treated with docetaxel(0-100umol/L), and cell growth and apoptosis were evaluated using MTT (3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyl tetrazolium bromide) assay (using adriamycin (0-50umol/L) as the control) and flowcytometry. Western blot analysis was used to measure the effect of docetaxel on phosphor-ERKl/2 expression in the two cell lines. Results: The expressions of ERct36 and ERα66 were detectable in both MCF-7/ERα66 and MCF-7/ERα36 cell lines, while the expression of ERα36 in MCF-7/ER36 cells was higher. Both docetaxel and adriamycin inhibited the proliferation of both cells lines in a dose and time dependent manner. In comparison with MCF-7/ERα36 cell line, the MCF-7/ERα66 cells produced greater growth inhibition and apoptosis after treatment with docetaxel, but there was no significant difference in growth inhibition between the two cell lines treated with adriamycin; The MCF-7/ERα36 cell line resulted in a significant activation (phosphorylation) of ERK1/2 after treatment with docetaxel in a dose-dependent manner, but in the MCF-7/ERα66 cell line , a decrease in the level of phosphor- ERK1/2 expression was observed as the dose of docetaxel increased. Conclusion: ERa36 may be an agent that weakens chemosensitivity to docetaxel in breast cancer, probably by activating the expression of ERKI/2.展开更多
OBJECTIVE To investigate the expression of the nuclear transcription factor NF-κB, ER, HER2 and PCNA in breast cancers, and to study the relationship between activation of NF-κB and clinicopathologic parameters incl...OBJECTIVE To investigate the expression of the nuclear transcription factor NF-κB, ER, HER2 and PCNA in breast cancers, and to study the relationship between activation of NF-κB and clinicopathologic parameters including the level of PCNA, ER, HER2, lymph node involvement, tumor size and histological grade (differentiation). METHODS Sixty cases of human breast cancer tissues and adjacent non-neoplastic breast tissues were examined for NF-κB, HER2 and ER, as well as PCNA by immunohistochemical methodS. In addition the clinicopathologic parameters of the patients including lymph node involvement, tumor size and histological grade (differentiation) were collected. RESULTS The expression of NF-κB in the breast cancers and adjacent non-neoplastic breast tissue was 50.0% (30/60) and 40.0% (24/60) respectively, resulting in no significant difference (P〉0.05). NF-κB and HER2 expression was positively correlated whereas NF-κB and ER expression was negatively correlated. The NF-κB activation was 77.8% (14/18) in the breast cancers that were ER-/HER2^+, a level significantly higher (P〈0.001) in comparison to the other groups of patients. The expression of NF-κB in the low-differentiated group (grade Ⅲ) was 57.1%, and in the moderate-differentiated group (grade Ⅱ) was 50.3%, both of which were higher than the 35.7% found in the high-differentiated group (grade Ⅰ). NF-κB activation in the cancers was significantly correlated with the histological grade (P〈0.05), PCNA expression (P=0.003) and lymph node involvement and tumor size (P=0.03 and 0.002, respectively). CONCLUSION NF-κB was activated abnormally in a portion of the breast cancers. The finding that NF-κB activation was positively correlated with HER2 expression, the level of PCNA, tumor grade, size and lymph node involvement is in accord with the ability of NF-κB to promote cellular proliferation and migration, clearly identifies the protein as a hallmark for targeted dysregulation in oncogenesis. NF-κB may be a hopeful target for breast cancer therapy.展开更多
Objective:To determine the influence of the single nucleotide polymorphism(SNP)rs4245739 on the binding and expression of micro RNAs and subsequent MDM4 expression and the correlation of these factors with clinical de...Objective:To determine the influence of the single nucleotide polymorphism(SNP)rs4245739 on the binding and expression of micro RNAs and subsequent MDM4 expression and the correlation of these factors with clinical determinants of ER-negative breast cancers.Methods:Find Tar and miRanda were used to detect the manner in which potential micro RNAs are affected by the SNP rs4245739-flanking sequence.RNA sequencing data for ER-negative breast cancer from The Cancer Genome Atlas(TCGA)were used to compare the expression of miR-184,miR-191,miR-193a,miR-378,and MDM4 in different rs4245739 genotypes.Results:Comparison of ER-negative cancer patients with and without the expression of miR-191 as well as profile micro RNAs(miR-184,miR-191,miR-193a and miR-378 altogether)can differentiate the expression of MDM4 among different rs4245739 genotypes.Although simple genotyping alone did not reveal significant clinical relationships,the combination of genotyping and micro RNA profiles was able to significantly differentiate individuals with larger tumor size and lower number of involved lymph nodes(P<0.05)in the risk group(A allele).Conclusions:We present two novel methods to analyze SNPs within 3′UTRs that use:(i)a single miRNA marker expression and(ii)an expression profile of miRNAs predicted to bind to the SNP region.We demonstrate that the application of these two methods,in particular the miRNA profile approach,permits detection of new molecular and clinical features related to the rs4245739 variant in ER-negative breast cancer.展开更多
Results of comparative study of Human Leu-cocytic Antigen (HLA-A), -B typing in 73 breast cancer (BC) patients having different estrogen receptor (ER) status and 50 healthy individuals in the northern part of China ar...Results of comparative study of Human Leu-cocytic Antigen (HLA-A), -B typing in 73 breast cancer (BC) patients having different estrogen receptor (ER) status and 50 healthy individuals in the northern part of China are reported. In 58 of the 73 patients, HLA-C, -DR typing were also studied in addition. The results of this study showed that HLA-Bw61 (40) were negatively associated with BC, while -Cw7 and -DRw6 were positively associated with BC. Moreover, -DR was more closely associated with ER(+) status with a RR value of 8.621. In the ER(-) group, there were no specific related antigens. In the light of the differences in pathology, prognosis and effect of endocrine therapy between ER(+) and ER(-) status, the authors are inclined to the view that the two kinds of breast cancer may be a heterogeneous disease.展开更多
Aim Recent evidence has revealed that Eukaryotic elongation factor-2 kinase (eEF2K) activity may confer cancer cell adaptation to metabolic stress, and high expression of eEF2K is found in several types of cancer. T...Aim Recent evidence has revealed that Eukaryotic elongation factor-2 kinase (eEF2K) activity may confer cancer cell adaptation to metabolic stress, and high expression of eEF2K is found in several types of cancer. Therefore, eEF2K may contribute to carcinogenesis and represent a promising therapeutic target; however, inhibi- tion of eEF2K for cancer drug discovery still remains in its infancy. This study aimed at developing a series of eEF2K inhibitor as candidate anti-tumor drugs in breast cancer and illustrating the possible mechanisms of its anti- tumor activity in vitro and in vivo. Methods In silico screening, structure modifications, MTT assay and molecular dynamics (MD) simulations were applied for the discovery of the novel eEF2K inhibitor (BL-EKI03). Observa- tions of cell morphology were executed through several methods including ER-traeker, MDC and Hoeehst 33258 staining and GFP-LC3 transfeetion. Flow eytometrie analyses of MDC and Annexin V/PI were used for quantifica- tion of autophagy and apoptosis ratio. Western blot and ITRAQ analysis were used to explore the detailed mecha- nisms of BL-EKI03-induced ER stress, autophagie death and apoptosis in breast cancer cells. Furthermore, an in vivo xenograft mouse model was established for validating the anti-tumor efficacy of BL-EKI03. Results Firstly, a novel eEF2K inhibitor (BL-EKI03) with a good affinity for eEF2K was eventually discovered after computational screening and synthesis of a series of candidate compounds targeting eEF2K. Subsequently, our results demonstra- ted that BL-EKI03 has remarkable anti-proliferative activities and induces endoplasmie retieulum (ER) stress, au- tophagy and apoptosis in MCF-7 and MDA-MB-436 cells. More importantly, the mechanism for BL-EKI03-indueed autophagie death involves eEF2K-mediated AMPK-mTOR-ULK complex pathways. The proteomies analyses and ex-perimental validation revealed that the BL-EKI03-induced mechanism was also involved BIRC6, BNIP1, SNAP29 and Bif-1, which might be regulated by eEF2K. Moreover, BL-EKI03 exerted its anti-tumor activities without re- markable toxicity, and it also induced autophagy and apoptosis by targeting eEF2K in fifo. Conclusion In this study, a novel eEF2K inhibitor (BL-EKI03) was discovered with remarkable anti-proliferative activities and in- duced endoplasmic reticulum (ER) stress, autophagy and apoptosis of breast cancer in vitro and in fifo. These findings highlight a new small-molecule eEF2K inhibitor (BL-EKI03) that has the potential to impact future breast cancer therapy.展开更多
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...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.展开更多
Objective: We studied the alterations in the expression of estrogen receptor alpha (ER) in the progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinomas (IDC). Methods: The mastectomy specimens of...Objective: We studied the alterations in the expression of estrogen receptor alpha (ER) in the progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinomas (IDC). Methods: The mastectomy specimens of 120 cases containing both DCIS and IDC were examined. The expression of ER proteins were examined by immunohistochemistry. The difference of the expression of ER proteins between DCIS and IDC were compared. Results: There were 58.33% of the cases with DCIS expressing ER proteins, and 40.00% of the cases IDC expressing ER proteins. There was a significant decrease of ER expression in IDC compared to DCIS (χ2 = 4.034, P = 0.045). Conclusion: These findings substantiate the notion that breast cancer progression is often associated with alterations in expressions of ER. The underlying mechanisms of these alterations need further investigation.展开更多
Objective: The purpose of the study was to investigate the relationship between the expression of estrogen receptor(ER), progestogen receptor(PR), human epidermal growth factor receptor(Her-2), Ki-67 and the effect of...Objective: The purpose of the study was to investigate the relationship between the expression of estrogen receptor(ER), progestogen receptor(PR), human epidermal growth factor receptor(Her-2), Ki-67 and the effect of neoadjuvant chemotherapy in breast cancer. Methods: The expression of ER, PR, Her-2 and Ki-67 in 45 breast cancers which received neoadjuvant chemotherapy was detected by immunohistochemistry. Results: The effective rates in ER negative and PR negative groups were higher than those in ER positive and PR positive groups(83.3% vs 59. 4%, 82.4% vs 60.6%). There was no significant difference of the effective rate between Her-2 overexpressed group and Her-2 non-overexpressed group(81.8% vs 64.1%), and the same thing happened between Ki-67 negative group and Ki-67 positive group(67.7% vs 63.2%). Conclusion: In the patients with breast cancer, ER, PR negative ones were more sensitive to neoadjuvant chemotherapy. These patients may get more benefits from chemotherapy. ER, PR could be feasible markers for predicting the effective rate of neoadjuvant chemotherapy.展开更多
Objective To elucidate the BRCA1 participated mechanism of genesis and development of sporadic breast cancer through detect the statues of BRCA1 and analysis the relationship with the pathologic and clinic parameters....Objective To elucidate the BRCA1 participated mechanism of genesis and development of sporadic breast cancer through detect the statues of BRCA1 and analysis the relationship with the pathologic and clinic parameters.Methods BRCA1 statues were respectively analyzed in frozen samples or paraffine fixed sporadic breast carcinoma and benign breast tissues by three methods:protein expression by immunohistochemistry(IHC),the methylation of BRCA1 promoter by methylation specific PCR(MSP),gene copy number by interphase fluorescence in situ hybridization(FISH).Results 14.2%(29/204)cases were detected hypermethylation of BRCA1 promoter in sporadic breast cancer.BRCA1 mean copy number in sporadic breast cancer(1.70±0.14)less than those in benign tissues(2.03±0.08,P<0.05),and in sporadic breast cancer with hypermethylation of BRCA1(1.62±0.09)significantly less than in those without hypermethylation(1.84±0.26,P<0.05).The loss copy related to the methylation of BRCA1 promoter.There were significant of 41.1%(88/214)cases no BRCA1 nuclei expression in sporadic breast cancers.Loss expression of BRCA1 had significant correlation with higher histological stages,axillary's lymph nodal metastasis(P<0.01),lower expression of ERα,and overexpression of HER-2 protein(P<0.01).Conclusions There are BRCA1 methylations,loss BRCA1 gene copy and loss protein expression in the sporadic breast cancer,the three statues of BRCA1 is correlated to each other;and the loss expression of BRCA1 protein related to part of pathology and clinic parameters.展开更多
基金the National Natural Science Foundation of China(Grant Nos:81272260&81572712 to L.Chen)Natural Science Fund for Distinguished Young Scholars of Jiangsu Province(SBK2020010058)the Priority Academic Program Development of Jiangsu Higher Education Institutions.
文摘Estrogen receptor alpha(ERα/ESR1)is overexpressed in over half of all breast cancers and is considered a valuable therapeutic target in ERαpositive breast cancer.Here,we designed a membrane-permeant Chaperonemediated Autophagy Targeting Chimeras(CMATAC)peptide to knockdown endogenous ERαprotein through chaperone-mediated autophagy.The peptide contains a cell membrane-penetrating peptide(TAT)that allows the peptide to by-pass the plasma membrane,anαI peptide as a protein-binding peptide(PBD)that binds specifically to ERα,and CMA-targeting peptide(CTM)that targeting chaperone-mediated autophagy.We validated that ERαtargeting peptide was able to target and degrade ERαto reduce the viability of ERαpositive breast cancer cells.Taken together,our studies provided a new method to reduce the level of intracellular ERαprotein via CMATAC,and thus may provide a new strategy for the treatment of ERαpositive breast cancer.
基金We thank Professor Wei Cheng(Dalian Medical University)for generously offering T47D,MCF7,ZR-75-1,and SK-BR-3 breast cancer cells and Professor WeiGuo Zhu(Peking University Health Science Center)for providing the full-length human Flag-CHD4,GFP-CHD4,and GST-CHD4 plasmids.
文摘The estrogen signaling system is a crucial regulator of metabolicandphysiologicalprocesses.However,abnormal activation of estrogen signaling may play a role in breast cancer initiation and progression.Crucial to this pathway is the interaction between estrogen receptor alpha(ERa)and various co-transcription activators.1 Although numerous studies have investigated ER coregulators,the protein-protein interaction networks of ERa are not fully understood.Recent research has shown that high chromodomain helicase DNA-binding 4(CHD4)expression is linked to poor prognosis in various cancers.2,?In this study,we demonstrated that both CHD4 and ERαcontribute to breast cancer progression while providing evidence of the regulatory processes and functional interplay between these two proteins.
文摘Estrogen receptor(ER) is a vital biomarker in the development and development of breast cancer, and its status has great clinical value in clinical treatment strategy, endocrine therapy efficacy prediction, and breast cancer prognosis. By specifically combining <sup>18</sup>F-FES with ER, <sup>18</sup>F-FES PET/CT imaging uses standard uptake value(SUV) to semi-quantitatively reflect the distribution of ER and its biological activity in patients, and assesses the expression of ER in breast cancer patients about primary and metastases before or after treatment, to provide a basis for personalized treatment of breast cancer. In this review, we will review the imaging principles of a new ER detection method <sup>18</sup>F-FES PET/CT, and the research progress in the clinical application of breast cancer, and compare its diagnostic and treatment value with non-specific tumor imaging <sup>18</sup>F-FDG PET/CT in breast cancer.
基金This work was supported by the Shanghai Shenkang Hospital Development Center’s Shenkang Promotion of Clin‑ical Skills and Clinical Innovation in Municipal Hospitals Three-Year Action Plan(No.2020‒2023)the Major Clinical Research Project(No.SHDC2020CR1048B)the Pilot Construction Project of High-Level Universities in Shanghai(No.DGF501017-06),China。
文摘Endoplasmic reticulum(ER)stress,as an emerging hallmark feature of cancer,has a considerable impact on cell proliferation,metastasis,invasion,and chemotherapy resistance.Ovarian cancer(OvCa)is one of the leading causes of cancer-related mortality across the world due to the late stage of disease at diagnosis.Studies have explored the influence of ER stress on OvCa in recent years,while the predictive role of ER stress-related genes in OvCa prognosis remains unexplored.Here,we enrolled 552 cases of ER stress-related genes involved in OvCa from The Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)cohorts for the screening of prognosis-related genes.The least absolute shrinkage and selection operator(LASSO)regression was applied to establish an ER stress-related risk signature based on the TCGA cohort.A seven-gene signature revealed a favorable predictive efficacy for the TCGA,International Cancer Genome Consortium(ICGC),and another GEO cohort(P<0.001,P<0.001,and P=0.04,respectively).Moreover,functional annotation indicated that this signature was enriched in cellular response and senescence,cytokines interaction,as well as multiple immune-associated terms.The immune infiltration profiles further delineated an immunologic unresponsive status in the high-risk group.In conclusion,ER stress-related genes are vital factors predicting the prognosis of OvCa,and possess great application potential in the clinic.
文摘Objective: To study the relationship between theexpression of PS, protein and Estrogen (ER) andProgesterone Receptor (PR) status and their prognoticvalue in breast canceL Methods: Using theimmunohistochemical method, PS2 protein expressionswere detected in 105 cases with breast cancer. Results:The positive rate of PS2 protein was 50.48% (53/105) in105 cases. The positive rate of PS, in the patients whosurvived five years or more was 56.96% (45/79), whichwas higher than that of those who lived less than fiveyears (30.77%, 8/26). In the ER, PR (+) patients, thepositive rate of PS, was higher (76.74%, 33/34), thanthat of those with ER, PR (-) (22.5%, 9/40). Conclusions:Our results suggest that the expression of PS, proteinwas positively correlated with the 5-year-survival andthat of ER and PR in breast cancer. It is considered thatPS, may be as a prognostic predictor, and detection ofPS, protein expression was useful for a guidingtreatment of breast cancer.
文摘他莫昔芬(tamoxifen,TAM)作为雌激素受体阳性(estrogen receptor,ER+)乳腺癌的一线化疗药物使大多数患者受益,但原发性和继发性耐药问题严重影响临床治疗效果。深入研究ER+乳腺癌TAM耐药机制,改善治疗效果是当前亟待解决的问题。抑癌因子NDRG2(N-myc downstream regulated gene 2,NDRG2)在肿瘤发生发展中发挥重要作用,但是否参与ER+乳腺癌TAM耐药尚不清楚。本研究旨在探明NDRG2在ER+乳腺癌TAM耐药中发挥的作用和机制。通过RT-PCR与免疫印迹分析对比TAM敏感型和耐药型ER+乳腺癌细胞发现,NDRG 2的mRNA转录水平和蛋白质翻译水平在TAM耐药细胞中表达显著下调,且与耐药能力负相关(P<0.001);CCK-8细胞毒性实验和软琼脂克隆形成实验证实,在耐药细胞中过表达NDRG2可显著降低TAM药物半抑制浓度IC 50和软琼脂克隆形成率(P<0.001),逆转耐药表型。分子机制上,X-box结合蛋白1(X-box binding protein 1,XBP1)mRNA剪切实验与内质网相关降解(endoplasmic-reticulum associated degradation,ERAD)报告蛋白的结果显示,过表达NDRG2可增强耐药细胞中剪切型XBP1s mRNA转录与ERAD报告蛋白CD3ε-YFP表达(P<0.001),引发耐药细胞内质网强应激反应;免疫印迹检测结果显示,过表达NDRG2可显著提高耐药细胞中内质网应激感受器肌醇需要激酶1α(inositol requiring enzyme 1,IRE1α)的磷酸化水平及其下游因子,例如内质网EIP辅助因子(endoplasmic reticulum-localized DnaJ 4,ERdj4)、PKR蛋白激酶的细胞抑制剂(cellular Inhibitor of the PKR protein kinase,P58 IPK)、α甘露糖苷酶样应激蛋白(er degradation enhancingαmannosidase likeprotein,EDEM)和蛋白质二硫键异构酶家族A成员5(protein disulfide isomerase family a member 5,PDIA5)的表达水平(P<0.001)。小鼠异种移植瘤研究进一步证实,在耐药细胞中过表达NDRG2可增强TAM治疗效果,显著抑制耐药移植瘤生长(P<0.001)。以上研究结果表明,通过提高耐药细胞中NDRG2表达,增强TAM治疗引发的内质网强烈应激,可逆转ER+乳腺癌细胞耐药性,改善TAM治疗效果。研究结果为解决ER+乳腺癌TAM耐药问题提供了新的思路和有价值的潜在药物靶点。
文摘Aim Breast cancer is one of the lethal gynecological malignancy in the world. Tamoxifen (TAM) and fulvestrant (FUL) are the major drugs for patients with estrogen receptor-positive (ER + ) breast cancers. Howev- er, the development of endocrine resistance is the impediment for successful treatment. In this study, we explored the mechanisms of endocrine resistance and therapeutic strategy for overcoming resistance against TAM and FUL. Methods The experiments were performed in Ell + and estrogen/TAM-sensitive MCF7 cells and antiestrogen-re- sistant MCF7/LCC9 cells. Western blot and confocal microscopy were used to determine cell autophagy. Cell trans- fection and luciferase activity assay were performed to identify the target gene of miR-214. Results It showed that 4-OHT/FUL treatment induced apoptosis as well as autophagy in breast cancer cells. The increase of autophagy might be the major cause of endocrine resistance to 4-OHT or FUL. Mill-214 increased the sensitivity of breast cancer cells to the 4-OHT/FUL-induced apoptosis through inhibition of autophagy. Importantly, a negative correla- tion was established between miR-214 and UCP2 in human breast cancer tissue specimens by RT-qPCR assay. UCP2 was identified to be a direct target of mill-214. Further study in MCF7/LCC9 cells indicated that endocrine resistance might arise from activation of the PI3 K-Akt-mTOll pathway, thereby inducing autophagy by overexpres- sion of UCP2. Conclusions MiR-214 increased the sensitivity of breast cancer cells to TAM and FUL through in- hibition of autophagy by targeting UCP2. Mill-214 shows potential as a novel therapeutic strategy for overcoming endocrine resistance in ER + breast cancers.
基金supported by the National Natural Science Foundation of China (No.30671508)by State Key Laboratory for Agrobiotechnology of China (No.2009SKLAB07-5)
文摘Objective: To investigate whether dietary daidzein interact with endogenous 17β-Estradiol (E2) to give rise to additive or inhibitory effects on proliferation and apoptosis in breast cancer cells. Methods: Cell cycle distribution and apoptosis induction were analyzed by using flow cytometry when breast cancer cell lines MCF-7 were cotreated with daidzein (1, 5 μmol/L) and E2 (0.1-10 nmol/L) for 5 days. Whether daidzein could alter E2-modulated mRNA expression of estrogen receptor alpha (ERα), estrogen receptor beta (ERI3) and ERβ-estrogen response element (ERE) dependent transcription was investigated by RT-PCR and luciferase induction assays. The effects of daidzein on E2-modulated expression of proapoptotic p53, bax and antiapoptotic bcl-2 at both mRNA and protein levels were also investigated by RT-PCR and Western blot. Results: Daidzein enhanced the antiapoptotic effect in an Ea dose-dependent manner, but had no effect on E2-induced proliferation. Daidzein antagonized E2-induced ERβ mRNA expression and ERβ-ERE dependent transcription. In addition, daidzein only antagonized E2-upregulated expression of p53 and bax, but had no effect on E2-upregulated expression of bcl-2. Conclusion: Daidzein enhances the antiapoptotic effect of E2 on breast cancer cells by inhibiting E2-mediated p53-bax proapoptotic pathway. These results suggest that dietary daidzein may enhance deleterious effect of endogenous E2 in hormone-dependent breast cancer.
文摘Objective: hER-α36 is a variant of estrogen receptor-a, identified and cloned by a team of American. This research is to determine whether hER-α36 can enhance or weaken chemosensitivity to docetaxel in breast cancer cell line MCF-7(ERα66 positive). Methods: RT-PCR was used to detect the expressions of ERα66 and ERa36 in the two human breast cancer cell lines MCF-7(MCF-7/ERα66) and MCF-7 transfected with ERa36(MCF-7/ERα36). The two cell lines were treated with docetaxel(0-100umol/L), and cell growth and apoptosis were evaluated using MTT (3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyl tetrazolium bromide) assay (using adriamycin (0-50umol/L) as the control) and flowcytometry. Western blot analysis was used to measure the effect of docetaxel on phosphor-ERKl/2 expression in the two cell lines. Results: The expressions of ERct36 and ERα66 were detectable in both MCF-7/ERα66 and MCF-7/ERα36 cell lines, while the expression of ERα36 in MCF-7/ER36 cells was higher. Both docetaxel and adriamycin inhibited the proliferation of both cells lines in a dose and time dependent manner. In comparison with MCF-7/ERα36 cell line, the MCF-7/ERα66 cells produced greater growth inhibition and apoptosis after treatment with docetaxel, but there was no significant difference in growth inhibition between the two cell lines treated with adriamycin; The MCF-7/ERα36 cell line resulted in a significant activation (phosphorylation) of ERK1/2 after treatment with docetaxel in a dose-dependent manner, but in the MCF-7/ERα66 cell line , a decrease in the level of phosphor- ERK1/2 expression was observed as the dose of docetaxel increased. Conclusion: ERa36 may be an agent that weakens chemosensitivity to docetaxel in breast cancer, probably by activating the expression of ERKI/2.
基金This work was supported by the National Natural Science Foundation of China (No. 30471962).
文摘OBJECTIVE To investigate the expression of the nuclear transcription factor NF-κB, ER, HER2 and PCNA in breast cancers, and to study the relationship between activation of NF-κB and clinicopathologic parameters including the level of PCNA, ER, HER2, lymph node involvement, tumor size and histological grade (differentiation). METHODS Sixty cases of human breast cancer tissues and adjacent non-neoplastic breast tissues were examined for NF-κB, HER2 and ER, as well as PCNA by immunohistochemical methodS. In addition the clinicopathologic parameters of the patients including lymph node involvement, tumor size and histological grade (differentiation) were collected. RESULTS The expression of NF-κB in the breast cancers and adjacent non-neoplastic breast tissue was 50.0% (30/60) and 40.0% (24/60) respectively, resulting in no significant difference (P〉0.05). NF-κB and HER2 expression was positively correlated whereas NF-κB and ER expression was negatively correlated. The NF-κB activation was 77.8% (14/18) in the breast cancers that were ER-/HER2^+, a level significantly higher (P〈0.001) in comparison to the other groups of patients. The expression of NF-κB in the low-differentiated group (grade Ⅲ) was 57.1%, and in the moderate-differentiated group (grade Ⅱ) was 50.3%, both of which were higher than the 35.7% found in the high-differentiated group (grade Ⅰ). NF-κB activation in the cancers was significantly correlated with the histological grade (P〈0.05), PCNA expression (P=0.003) and lymph node involvement and tumor size (P=0.03 and 0.002, respectively). CONCLUSION NF-κB was activated abnormally in a portion of the breast cancers. The finding that NF-κB activation was positively correlated with HER2 expression, the level of PCNA, tumor grade, size and lymph node involvement is in accord with the ability of NF-κB to promote cellular proliferation and migration, clearly identifies the protein as a hallmark for targeted dysregulation in oncogenesis. NF-κB may be a hopeful target for breast cancer therapy.
基金supported by grants from UK Medical Research Councils(Grant No.MC_UU_12019/2 and MC_UU_12019/4)Sumadi Lukman Anwar received a grant from PTUPT(Grant No.Ristekdikti 09_18)
文摘Objective:To determine the influence of the single nucleotide polymorphism(SNP)rs4245739 on the binding and expression of micro RNAs and subsequent MDM4 expression and the correlation of these factors with clinical determinants of ER-negative breast cancers.Methods:Find Tar and miRanda were used to detect the manner in which potential micro RNAs are affected by the SNP rs4245739-flanking sequence.RNA sequencing data for ER-negative breast cancer from The Cancer Genome Atlas(TCGA)were used to compare the expression of miR-184,miR-191,miR-193a,miR-378,and MDM4 in different rs4245739 genotypes.Results:Comparison of ER-negative cancer patients with and without the expression of miR-191 as well as profile micro RNAs(miR-184,miR-191,miR-193a and miR-378 altogether)can differentiate the expression of MDM4 among different rs4245739 genotypes.Although simple genotyping alone did not reveal significant clinical relationships,the combination of genotyping and micro RNA profiles was able to significantly differentiate individuals with larger tumor size and lower number of involved lymph nodes(P<0.05)in the risk group(A allele).Conclusions:We present two novel methods to analyze SNPs within 3′UTRs that use:(i)a single miRNA marker expression and(ii)an expression profile of miRNAs predicted to bind to the SNP region.We demonstrate that the application of these two methods,in particular the miRNA profile approach,permits detection of new molecular and clinical features related to the rs4245739 variant in ER-negative breast cancer.
文摘Results of comparative study of Human Leu-cocytic Antigen (HLA-A), -B typing in 73 breast cancer (BC) patients having different estrogen receptor (ER) status and 50 healthy individuals in the northern part of China are reported. In 58 of the 73 patients, HLA-C, -DR typing were also studied in addition. The results of this study showed that HLA-Bw61 (40) were negatively associated with BC, while -Cw7 and -DRw6 were positively associated with BC. Moreover, -DR was more closely associated with ER(+) status with a RR value of 8.621. In the ER(-) group, there were no specific related antigens. In the light of the differences in pathology, prognosis and effect of endocrine therapy between ER(+) and ER(-) status, the authors are inclined to the view that the two kinds of breast cancer may be a heterogeneous disease.
文摘Aim Recent evidence has revealed that Eukaryotic elongation factor-2 kinase (eEF2K) activity may confer cancer cell adaptation to metabolic stress, and high expression of eEF2K is found in several types of cancer. Therefore, eEF2K may contribute to carcinogenesis and represent a promising therapeutic target; however, inhibi- tion of eEF2K for cancer drug discovery still remains in its infancy. This study aimed at developing a series of eEF2K inhibitor as candidate anti-tumor drugs in breast cancer and illustrating the possible mechanisms of its anti- tumor activity in vitro and in vivo. Methods In silico screening, structure modifications, MTT assay and molecular dynamics (MD) simulations were applied for the discovery of the novel eEF2K inhibitor (BL-EKI03). Observa- tions of cell morphology were executed through several methods including ER-traeker, MDC and Hoeehst 33258 staining and GFP-LC3 transfeetion. Flow eytometrie analyses of MDC and Annexin V/PI were used for quantifica- tion of autophagy and apoptosis ratio. Western blot and ITRAQ analysis were used to explore the detailed mecha- nisms of BL-EKI03-induced ER stress, autophagie death and apoptosis in breast cancer cells. Furthermore, an in vivo xenograft mouse model was established for validating the anti-tumor efficacy of BL-EKI03. Results Firstly, a novel eEF2K inhibitor (BL-EKI03) with a good affinity for eEF2K was eventually discovered after computational screening and synthesis of a series of candidate compounds targeting eEF2K. Subsequently, our results demonstra- ted that BL-EKI03 has remarkable anti-proliferative activities and induces endoplasmie retieulum (ER) stress, au- tophagy and apoptosis in MCF-7 and MDA-MB-436 cells. More importantly, the mechanism for BL-EKI03-indueed autophagie death involves eEF2K-mediated AMPK-mTOR-ULK complex pathways. The proteomies analyses and ex-perimental validation revealed that the BL-EKI03-induced mechanism was also involved BIRC6, BNIP1, SNAP29 and Bif-1, which might be regulated by eEF2K. Moreover, BL-EKI03 exerted its anti-tumor activities without re- markable toxicity, and it also induced autophagy and apoptosis by targeting eEF2K in fifo. Conclusion In this study, a novel eEF2K inhibitor (BL-EKI03) was discovered with remarkable anti-proliferative activities and in- duced endoplasmic reticulum (ER) stress, autophagy and apoptosis of breast cancer in vitro and in fifo. These findings highlight a new small-molecule eEF2K inhibitor (BL-EKI03) that has the potential to impact future breast cancer therapy.
文摘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.
基金Supported by a grant from the National Science Foundation of China (No. 30772100)
文摘Objective: We studied the alterations in the expression of estrogen receptor alpha (ER) in the progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinomas (IDC). Methods: The mastectomy specimens of 120 cases containing both DCIS and IDC were examined. The expression of ER proteins were examined by immunohistochemistry. The difference of the expression of ER proteins between DCIS and IDC were compared. Results: There were 58.33% of the cases with DCIS expressing ER proteins, and 40.00% of the cases IDC expressing ER proteins. There was a significant decrease of ER expression in IDC compared to DCIS (χ2 = 4.034, P = 0.045). Conclusion: These findings substantiate the notion that breast cancer progression is often associated with alterations in expressions of ER. The underlying mechanisms of these alterations need further investigation.
文摘Objective: The purpose of the study was to investigate the relationship between the expression of estrogen receptor(ER), progestogen receptor(PR), human epidermal growth factor receptor(Her-2), Ki-67 and the effect of neoadjuvant chemotherapy in breast cancer. Methods: The expression of ER, PR, Her-2 and Ki-67 in 45 breast cancers which received neoadjuvant chemotherapy was detected by immunohistochemistry. Results: The effective rates in ER negative and PR negative groups were higher than those in ER positive and PR positive groups(83.3% vs 59. 4%, 82.4% vs 60.6%). There was no significant difference of the effective rate between Her-2 overexpressed group and Her-2 non-overexpressed group(81.8% vs 64.1%), and the same thing happened between Ki-67 negative group and Ki-67 positive group(67.7% vs 63.2%). Conclusion: In the patients with breast cancer, ER, PR negative ones were more sensitive to neoadjuvant chemotherapy. These patients may get more benefits from chemotherapy. ER, PR could be feasible markers for predicting the effective rate of neoadjuvant chemotherapy.
文摘Objective To elucidate the BRCA1 participated mechanism of genesis and development of sporadic breast cancer through detect the statues of BRCA1 and analysis the relationship with the pathologic and clinic parameters.Methods BRCA1 statues were respectively analyzed in frozen samples or paraffine fixed sporadic breast carcinoma and benign breast tissues by three methods:protein expression by immunohistochemistry(IHC),the methylation of BRCA1 promoter by methylation specific PCR(MSP),gene copy number by interphase fluorescence in situ hybridization(FISH).Results 14.2%(29/204)cases were detected hypermethylation of BRCA1 promoter in sporadic breast cancer.BRCA1 mean copy number in sporadic breast cancer(1.70±0.14)less than those in benign tissues(2.03±0.08,P<0.05),and in sporadic breast cancer with hypermethylation of BRCA1(1.62±0.09)significantly less than in those without hypermethylation(1.84±0.26,P<0.05).The loss copy related to the methylation of BRCA1 promoter.There were significant of 41.1%(88/214)cases no BRCA1 nuclei expression in sporadic breast cancers.Loss expression of BRCA1 had significant correlation with higher histological stages,axillary's lymph nodal metastasis(P<0.01),lower expression of ERα,and overexpression of HER-2 protein(P<0.01).Conclusions There are BRCA1 methylations,loss BRCA1 gene copy and loss protein expression in the sporadic breast cancer,the three statues of BRCA1 is correlated to each other;and the loss expression of BRCA1 protein related to part of pathology and clinic parameters.