Retinoic acid receptor responder 3(RARRES3)has been characterized as a tumor suppressor in multiple types of cancer.This study aimed to examine the expression profile of RARRES3 across the PAM50 subtypes of breast can...Retinoic acid receptor responder 3(RARRES3)has been characterized as a tumor suppressor in multiple types of cancer.This study aimed to examine the expression profile of RARRES3 across the PAM50 subtypes of breast cancer.The DNA methylation status of RARRES3 was checked in the basal-like subtype,and the underlying mechanisms of its dysregulation were explored.RNA-sequencing(seq)and methylation data from The Cancer Genome Atlas were used for in-silico analysis.Basal-like representative SUM149 and MDA-MB-468 cell lines were used for in vitro and in vivo studies.Compared to tumor-adjacent normal tissues,only the basal-like tumor tissues had significantly downregulated RARRES3 expression.The methylation level of four CpG sites in the promoter region showed a strong negative correlation with RARRES3 expression.The gene coding for DNA methyltransferase 3A(DNMT3A)had consistent positive correlations with the methylation of the CpG sites.Chromatin Immunoprecipitation-quantitative polymerase chain-reaction and bisulfite sequencing PCR showed that DNMT3A could bind to the promoter region of RARRES3 and promote methylation of the CpG sites within the region.DNMT3A knockdown significantly restored RARRES3 expression at the mRNA and protein level in the two cell lines.CCK-8,colony formation,and flow cytometric analysis showed that RARRES3 overexpression attenuated the growth-promoting effects of DNMT3A overexpression and also weakened the DNMT3A overexpression-induced activation of ERK1/2 and PI3K/AKT signaling.In summary,this study revealed that DNMT3A enhances promoter methylation of the RARRES3 gene and suppresses its transcription in basal-like breast cancer.The DNMT3A-RARRES3 signaling pathway might be a potential target for the treatment of this tumor subtype.展开更多
The Triple Negative “Basal-like” breast cancer (TNBL) tumours have a high proliferative capacity and develop a resistance phenotype associated with metastases. However, the management of TNBL carcinomas is still not...The Triple Negative “Basal-like” breast cancer (TNBL) tumours have a high proliferative capacity and develop a resistance phenotype associated with metastases. However, the management of TNBL carcinomas is still not standardized. Among the promising trails, gold nanoparticles could be a relevant tool for the development of a targeted treatment for this breast cancer subtype in monotherapy, associated and/or conjugated with other drugs. In this work, we report the cytotoxicity impact of gold nanoparticles wrapped in Poly-Ethylene Glycol (PEG) on the TNBL HCC-1937 breast cancer cell line. PEG-coated gold nanoparticles (PEG-Au NPs) were synthesized by a two-step method using a reduction process followed by a post-functionalization called PEGylation. PEG-Au NPs were characterized using transmission electron microscopy and X-ray diffraction. The gold content of the samples was determined using atomic absorption spectrometer. The cytotoxicity tests were performed using Sulforhodamine B survival test and resazurin viability test. PEG-Au NPs impact analysis on HCC1937 TNBL cell line showed a clear toxic action of type dose dependent and at long term. These PEGylated gold nanoparticles present a promising tool for the development of tumor-specific radiosensitizing vectors, with or without the association of other treatment strategies.展开更多
High levels of tubulin expression have been described in a variety of human malignant tumors, and glu-tubulin, in which the C-terminal tyrosine of α-tubulin is removed by tubulin carboxypeptidase. Over-expression has...High levels of tubulin expression have been described in a variety of human malignant tumors, and glu-tubulin, in which the C-terminal tyrosine of α-tubulin is removed by tubulin carboxypeptidase. Over-expression has been reported in the malignant tumors of the mammary gland and correlated with poor prognosis immunohistochemically. Furthermore, Nielsen et al. proposed that the use of a panel of four markers (ER, HER 2, CK 5/6, and EGFR) could accurately identify basal-like phenotype carcinoma (BPC) with widely available standard pathologic tools. In our study, major prognostic factors such as patient age, tumor size, histological grade, axillary lymph node metastasis, vessel invasion, and local recurrence in BPC were not significantly different from non BP carcinoma (NBPC). However, the BPC group showed a higher ratio of distant metastasis than that of the NBPC group. In triple-negative carcinoma (TNC) cases, staining for glu-tubulin was observed in 46 cases (63.8%), which consisted of 42 of the 58 BPC patients (72.4%) and 4 of the 14 NBPC patients (28.6%). A significant association was found between the expression of glu-tubulin and BPC, but not NBPC. It seems that our findings also agree with the observation that BPC exhibits aggressive biological behavior and increases the content of glu-tubulin, which plays a greater role in migration and invasion.展开更多
Ductal carcinoma in situ(DCIS) is a category of early stage, non-invasive breast tumor defined by the intraductal proliferation of malignant breast epithelial cells. DCIS is a heterogeneous disease composed of multipl...Ductal carcinoma in situ(DCIS) is a category of early stage, non-invasive breast tumor defined by the intraductal proliferation of malignant breast epithelial cells. DCIS is a heterogeneous disease composed of multiple molecular subtypes including luminal, HER2 and basal-like types, which are characterized by immunohistochemical analyses and gene expression profiling. Following surgical and radiation therapies, patients with luminal-type, estrogen receptor-positive DCIS breast tumors can benefit from adjuvant endocrine-based treatment. However, there are no available targeted therapies for patients with basal-like DCIS(BL-DCIS) tumors due to their frequent lack of endocrine receptors and HER2 amplification, rendering them potentially susceptible to recurrence. Moreover, multiple lines of evidence suggest that DCIS is a non-obligate precursor of invasive breast carcinoma. This raises the possibility that targeting precursor BL-DCIS is a promising strategy to prevent BL-DCIS patients from the development of invasive basal-like breast cancer. An accumulating body of evidence demonstrates the existence of cancer stemlike cells(CSCs) in BL-DCIS, which potentially determine the features of BL-DCIS and their ability to progress into invasive cancer. This review encompasses the current knowledge in regard to the characteristics of BL-DCIS, identification of CSCs, and their biological properties in BL-DCIS. We summarize recently discovered relevant molecular signaling alterations that promote the generation of CSCs in BL-DCIS and the progression of BLDCIS to invasive breast cancer, as well as the influence of the tissue microenvironment on CSCs and the invasive transition. Finally, we discuss the translational implications of these findings for the prognosis and prevention of BL-DCIS relapse and progression.展开更多
Basal-like breast cancer with a luminal progenitor gene expression profile is an aggressive subtype of breast cancer with a poorer prognosis compared with other subtypes.However,genes that specifically promote basal-l...Basal-like breast cancer with a luminal progenitor gene expression profile is an aggressive subtype of breast cancer with a poorer prognosis compared with other subtypes.However,genes that specifically promote basal-like breast cancer development remain largely unknown.Here,we report that a novel gene C1orf106 plays an important role in maintaining the feature of basal-like/luminal progenitors.C1orf106 is frequently amplified and overexpressed in basal-like breast cancer and is associated with a poor outcome in patients.In human TCGA database,C1orf106 expression was correlated with upregulation of ELF5 and downregulation of GATA3,two transcription factors that regulate mammary gland stem cell fate.Enhanced expression of C1orf106 promotes tumor progression and expression of basal-like/luminal progenitor marker ELF5;depletion of C1orf106 suppresses tumorigenesis and expression of basal-like/luminal progenitor marker GATA3.These findings suggest that C1orf106 maintains the basal-like/luminal progenitor character through balancing the expression of ELF5 and GATA3.Taken together,we demonstrated that C1orf106 is an important regulator for basal-like/luminal progenitors and targeting C1orf106 is of therapeutic value for breast cancer.展开更多
Subject Code:H16With the support by the National Natural Science Foundation of China,a study by the research groups led by Prof.Dong Chenfang(董辰方)from Zhejiang University School of Medicine demonstrates that AKR1B1...Subject Code:H16With the support by the National Natural Science Foundation of China,a study by the research groups led by Prof.Dong Chenfang(董辰方)from Zhejiang University School of Medicine demonstrates that AKR1B1promotes basal-like breast cancer progression by apositive feedback loop that activates the展开更多
目的整合生物信息学挖掘并分析与基底型乳腺癌(basal-like breast cancer,BLBC)的预后相关的核心基因。方法首先,从GEO数据库中遴选与乳腺癌分子分型相关的数据集,数据处理后利用WGCNA筛选与BLBC相关的模块。然后,借助蛋白-蛋白互作(pro...目的整合生物信息学挖掘并分析与基底型乳腺癌(basal-like breast cancer,BLBC)的预后相关的核心基因。方法首先,从GEO数据库中遴选与乳腺癌分子分型相关的数据集,数据处理后利用WGCNA筛选与BLBC相关的模块。然后,借助蛋白-蛋白互作(protein-protein interaction,PPI)网络和cytohubba筛选出模块中差异最大的前10%基因作为候选基因,对候选基因进行生存分析和表达分析得到核心基因。最后,利用TIMER、TISIDB等生信工具探索核心基因表达和肿瘤免疫浸润、趋化因子及免疫调节剂的相关性并构建核心基因转录调控网络。结果利用WGCNA筛选出与BLBC相关的黑色模块中共891个基因,从差异性最大的80个候选基因中分析获得ESPL1和CCNB2两个核心基因。结果显示,两个核心基因与BLBC免疫细胞浸润有关,主要包括Th2细胞、CD8+T细胞、内皮细胞和肿瘤相关成纤维细胞。而且,核心基因表达水平与趋化因子、免疫刺激因子、免疫抑制因子及MHC分子相关。核心基因上游转录调控网络表明22种转录因子同时调控两个核心基因。结论ESPL1和CCNB2是BLBC的预后标志物且与肿瘤免疫相关。展开更多
目的探讨CIP2A、c-myc在基底细胞样乳腺癌(basal-like breast carcinoma,BLBC)、非基底细胞样乳腺癌(non-basal-likebreast cancer,NON-BLBC)及正常乳腺组织中的表达及其之间的相互关系。方法采用免疫组化MaxVision两步法对43例BLBC、53...目的探讨CIP2A、c-myc在基底细胞样乳腺癌(basal-like breast carcinoma,BLBC)、非基底细胞样乳腺癌(non-basal-likebreast cancer,NON-BLBC)及正常乳腺组织中的表达及其之间的相互关系。方法采用免疫组化MaxVision两步法对43例BLBC、53例NON-BLBC及20例正常乳腺组织中CIP2A、c-myc的表达进行检测。结果 CIP2A、c-myc蛋白在BLBC中的表达明显高于正常乳腺组织,且与BLBC淋巴结转移及临床分期有关,差异均有统计学意义(P<0.05)。CIP2A与c-myc蛋白的表达呈正相关(r=0.446,P<0.01)。结论 CIP2A可能与BLBC的发生、发展相关,且进一步支持CIP2A与c-myc之间的正反馈调节作用。展开更多
目的观察基底细胞样乳腺癌(basal-like breast carcinoma,BLBCs)的形态学和免疫组织化学特征,并探讨其诊断标准。方法对45例BLBCs与15例腔A型乳腺癌进行形态学观察及免疫组化检测,使用一抗包括CK5/6、CK14、SMA、CD10、p63、CD117、EGFR...目的观察基底细胞样乳腺癌(basal-like breast carcinoma,BLBCs)的形态学和免疫组织化学特征,并探讨其诊断标准。方法对45例BLBCs与15例腔A型乳腺癌进行形态学观察及免疫组化检测,使用一抗包括CK5/6、CK14、SMA、CD10、p63、CD117、EGFR、Vim、cyclin E、SKP2、Ki-67等指标。结果BLBCs形态学特征主要有:推进性生长方式(P=0.000);肿瘤间质有不同程度的淋巴细胞浸润(P=0.000);地图样坏死(P=0.000);非典型髓样癌特征(P=0.015);泡状核样(P=0.017);核分裂象多见(P=0.000);BLBCs高度表达以下免疫指标:CK5/6(P=0.000)、Vim(P=0.000)、CD117(P=0.018)、cyclin E(P=0.000)、SKP2(P=0.007)。结论BLBCs是经基因表型证实的一种特殊亚型的乳腺浸润性癌,形态学特征结合免疫组化特点可替代性诊断BLBCs。展开更多
基金supported by the Science&Technology Department of Sichuan Province,China(2022YFS0314).
文摘Retinoic acid receptor responder 3(RARRES3)has been characterized as a tumor suppressor in multiple types of cancer.This study aimed to examine the expression profile of RARRES3 across the PAM50 subtypes of breast cancer.The DNA methylation status of RARRES3 was checked in the basal-like subtype,and the underlying mechanisms of its dysregulation were explored.RNA-sequencing(seq)and methylation data from The Cancer Genome Atlas were used for in-silico analysis.Basal-like representative SUM149 and MDA-MB-468 cell lines were used for in vitro and in vivo studies.Compared to tumor-adjacent normal tissues,only the basal-like tumor tissues had significantly downregulated RARRES3 expression.The methylation level of four CpG sites in the promoter region showed a strong negative correlation with RARRES3 expression.The gene coding for DNA methyltransferase 3A(DNMT3A)had consistent positive correlations with the methylation of the CpG sites.Chromatin Immunoprecipitation-quantitative polymerase chain-reaction and bisulfite sequencing PCR showed that DNMT3A could bind to the promoter region of RARRES3 and promote methylation of the CpG sites within the region.DNMT3A knockdown significantly restored RARRES3 expression at the mRNA and protein level in the two cell lines.CCK-8,colony formation,and flow cytometric analysis showed that RARRES3 overexpression attenuated the growth-promoting effects of DNMT3A overexpression and also weakened the DNMT3A overexpression-induced activation of ERK1/2 and PI3K/AKT signaling.In summary,this study revealed that DNMT3A enhances promoter methylation of the RARRES3 gene and suppresses its transcription in basal-like breast cancer.The DNMT3A-RARRES3 signaling pathway might be a potential target for the treatment of this tumor subtype.
文摘The Triple Negative “Basal-like” breast cancer (TNBL) tumours have a high proliferative capacity and develop a resistance phenotype associated with metastases. However, the management of TNBL carcinomas is still not standardized. Among the promising trails, gold nanoparticles could be a relevant tool for the development of a targeted treatment for this breast cancer subtype in monotherapy, associated and/or conjugated with other drugs. In this work, we report the cytotoxicity impact of gold nanoparticles wrapped in Poly-Ethylene Glycol (PEG) on the TNBL HCC-1937 breast cancer cell line. PEG-coated gold nanoparticles (PEG-Au NPs) were synthesized by a two-step method using a reduction process followed by a post-functionalization called PEGylation. PEG-Au NPs were characterized using transmission electron microscopy and X-ray diffraction. The gold content of the samples was determined using atomic absorption spectrometer. The cytotoxicity tests were performed using Sulforhodamine B survival test and resazurin viability test. PEG-Au NPs impact analysis on HCC1937 TNBL cell line showed a clear toxic action of type dose dependent and at long term. These PEGylated gold nanoparticles present a promising tool for the development of tumor-specific radiosensitizing vectors, with or without the association of other treatment strategies.
文摘High levels of tubulin expression have been described in a variety of human malignant tumors, and glu-tubulin, in which the C-terminal tyrosine of α-tubulin is removed by tubulin carboxypeptidase. Over-expression has been reported in the malignant tumors of the mammary gland and correlated with poor prognosis immunohistochemically. Furthermore, Nielsen et al. proposed that the use of a panel of four markers (ER, HER 2, CK 5/6, and EGFR) could accurately identify basal-like phenotype carcinoma (BPC) with widely available standard pathologic tools. In our study, major prognostic factors such as patient age, tumor size, histological grade, axillary lymph node metastasis, vessel invasion, and local recurrence in BPC were not significantly different from non BP carcinoma (NBPC). However, the BPC group showed a higher ratio of distant metastasis than that of the NBPC group. In triple-negative carcinoma (TNC) cases, staining for glu-tubulin was observed in 46 cases (63.8%), which consisted of 42 of the 58 BPC patients (72.4%) and 4 of the 14 NBPC patients (28.6%). A significant association was found between the expression of glu-tubulin and BPC, but not NBPC. It seems that our findings also agree with the observation that BPC exhibits aggressive biological behavior and increases the content of glu-tubulin, which plays a greater role in migration and invasion.
基金Supported by The National Cancer Institute(NCI)of National Institutes of Health(NIH)of the United States of America to Zhou Q,Nos.5R01CA157779-03 and 5R01CA163820-04
文摘Ductal carcinoma in situ(DCIS) is a category of early stage, non-invasive breast tumor defined by the intraductal proliferation of malignant breast epithelial cells. DCIS is a heterogeneous disease composed of multiple molecular subtypes including luminal, HER2 and basal-like types, which are characterized by immunohistochemical analyses and gene expression profiling. Following surgical and radiation therapies, patients with luminal-type, estrogen receptor-positive DCIS breast tumors can benefit from adjuvant endocrine-based treatment. However, there are no available targeted therapies for patients with basal-like DCIS(BL-DCIS) tumors due to their frequent lack of endocrine receptors and HER2 amplification, rendering them potentially susceptible to recurrence. Moreover, multiple lines of evidence suggest that DCIS is a non-obligate precursor of invasive breast carcinoma. This raises the possibility that targeting precursor BL-DCIS is a promising strategy to prevent BL-DCIS patients from the development of invasive basal-like breast cancer. An accumulating body of evidence demonstrates the existence of cancer stemlike cells(CSCs) in BL-DCIS, which potentially determine the features of BL-DCIS and their ability to progress into invasive cancer. This review encompasses the current knowledge in regard to the characteristics of BL-DCIS, identification of CSCs, and their biological properties in BL-DCIS. We summarize recently discovered relevant molecular signaling alterations that promote the generation of CSCs in BL-DCIS and the progression of BLDCIS to invasive breast cancer, as well as the influence of the tissue microenvironment on CSCs and the invasive transition. Finally, we discuss the translational implications of these findings for the prognosis and prevention of BL-DCIS relapse and progression.
基金supported by the Ministry of Science and Technology of China (2016YFC1302103 and 2015CB553906)the National Natural Science Foundation of China (81230051, 81472734,31170711, 81321003, and 30830048)+3 种基金the Beijing Natural Science Foundation (7120002)the 111 Project of the Ministry of Education, Peking University (BMU2018JC004, BMU20120314, and BMU20130364)a Leading Academic Discipline Project of Beijing Education Bureau to H.Za grant from the National Natural Science Foundation of China (81773199) to J.Z
文摘Basal-like breast cancer with a luminal progenitor gene expression profile is an aggressive subtype of breast cancer with a poorer prognosis compared with other subtypes.However,genes that specifically promote basal-like breast cancer development remain largely unknown.Here,we report that a novel gene C1orf106 plays an important role in maintaining the feature of basal-like/luminal progenitors.C1orf106 is frequently amplified and overexpressed in basal-like breast cancer and is associated with a poor outcome in patients.In human TCGA database,C1orf106 expression was correlated with upregulation of ELF5 and downregulation of GATA3,two transcription factors that regulate mammary gland stem cell fate.Enhanced expression of C1orf106 promotes tumor progression and expression of basal-like/luminal progenitor marker ELF5;depletion of C1orf106 suppresses tumorigenesis and expression of basal-like/luminal progenitor marker GATA3.These findings suggest that C1orf106 maintains the basal-like/luminal progenitor character through balancing the expression of ELF5 and GATA3.Taken together,we demonstrated that C1orf106 is an important regulator for basal-like/luminal progenitors and targeting C1orf106 is of therapeutic value for breast cancer.
文摘Subject Code:H16With the support by the National Natural Science Foundation of China,a study by the research groups led by Prof.Dong Chenfang(董辰方)from Zhejiang University School of Medicine demonstrates that AKR1B1promotes basal-like breast cancer progression by apositive feedback loop that activates the
文摘目的整合生物信息学挖掘并分析与基底型乳腺癌(basal-like breast cancer,BLBC)的预后相关的核心基因。方法首先,从GEO数据库中遴选与乳腺癌分子分型相关的数据集,数据处理后利用WGCNA筛选与BLBC相关的模块。然后,借助蛋白-蛋白互作(protein-protein interaction,PPI)网络和cytohubba筛选出模块中差异最大的前10%基因作为候选基因,对候选基因进行生存分析和表达分析得到核心基因。最后,利用TIMER、TISIDB等生信工具探索核心基因表达和肿瘤免疫浸润、趋化因子及免疫调节剂的相关性并构建核心基因转录调控网络。结果利用WGCNA筛选出与BLBC相关的黑色模块中共891个基因,从差异性最大的80个候选基因中分析获得ESPL1和CCNB2两个核心基因。结果显示,两个核心基因与BLBC免疫细胞浸润有关,主要包括Th2细胞、CD8+T细胞、内皮细胞和肿瘤相关成纤维细胞。而且,核心基因表达水平与趋化因子、免疫刺激因子、免疫抑制因子及MHC分子相关。核心基因上游转录调控网络表明22种转录因子同时调控两个核心基因。结论ESPL1和CCNB2是BLBC的预后标志物且与肿瘤免疫相关。
文摘目的观察基底细胞样乳腺癌(basal-like breast carcinoma,BLBCs)的形态学和免疫组织化学特征,并探讨其诊断标准。方法对45例BLBCs与15例腔A型乳腺癌进行形态学观察及免疫组化检测,使用一抗包括CK5/6、CK14、SMA、CD10、p63、CD117、EGFR、Vim、cyclin E、SKP2、Ki-67等指标。结果BLBCs形态学特征主要有:推进性生长方式(P=0.000);肿瘤间质有不同程度的淋巴细胞浸润(P=0.000);地图样坏死(P=0.000);非典型髓样癌特征(P=0.015);泡状核样(P=0.017);核分裂象多见(P=0.000);BLBCs高度表达以下免疫指标:CK5/6(P=0.000)、Vim(P=0.000)、CD117(P=0.018)、cyclin E(P=0.000)、SKP2(P=0.007)。结论BLBCs是经基因表型证实的一种特殊亚型的乳腺浸润性癌,形态学特征结合免疫组化特点可替代性诊断BLBCs。
