三阴乳腺癌临床病理特征与分子标志物的相关性

三阴乳腺癌(triple-negative breast cancer,TNBC)即雌激素受体(estrogen receptor,ER)、孕激素受体(progestogen receptor,PR)、人表皮生长因子受体-2(human epithelial growth factor receptor-2,HER-2)均为阴性的乳腺癌.对内分泌治疗和抗HER-2的治疗无效,其分子亚型较多,存在基因表达差异,异质性明显,缺乏有效的分子靶标,且具有较高的侵袭转移率及复发率、预后差,临床病理学特征独特,因此探寻TNBC的临床病理特征及其分子标志物,对临床进一步诊断及治疗TNBC具有重要意义.     

靶向TAM在三阴性乳腺癌治疗中的研究进展

三阴性乳腺癌(triple negative breast cancer,TNBC)是乳腺癌中预后最差的类型,严重威胁女性生命健康。化疗和免疫治疗是TNBC最常用的治疗手段。目前临床使用抗程序性死亡受体1(programmed cell death protein 1,PD-1)和抗程序性死亡配体1(programme...     

三阴性乳腺癌中EpCAM和Sox2的表达及临床意义

目的：探讨 EpCAM 和 Sox2在三阴性乳腺癌( triple negative breast cancer, TNBC)中的表达及临床意义。方法采用免疫组化SP法检测EpCAM和Sox2在81例TNBC、71例非三阴性乳腺癌( non-triple-negative breast cancer, non-TN-BC)、20例癌旁正常乳腺组织中的表达。结果 TNBC组织中EpCAM、Sox2的阳性过表达率分别为74.1%、54.3%,均高于正常乳腺组织(15.0%和0)(P<0.05);EpCAM蛋白过表达与TNBC 的组织学分级、淋巴结转移呈正相关( P <0.05);Sox2蛋白表达与TNBC淋巴结转移、pTNM分期呈正相关( P<0.05)。 EpCAM 和 Sox2蛋白表达可能具有相关性。结论 EpCAM和Sox2蛋白在TNBC中均高表达,可能具有促癌作用及与淋巴结转移相关。     

三阴性乳腺癌中DBC2的表达及其临床病理意义

目的探讨乳腺癌缺失基因2(deleted in breast cancer2,DBC2)在三阴性乳腺癌(triple-negative breast cancer,TNBC)中的表达,分析其临床病理学意义。方法收集195例乳腺癌标本,采用免疫组化SP法检测38例TNBC、50例非三阴性乳腺癌(non-triple negative breast cancer,NTNBC)和30例正常乳腺组织中DBC2的表达;应用荧光原位杂交技术(fluorescent in situ hybridization,FISH)检测38例TNBC中HER-2基因扩增。结果正常乳腺组织中仅2例DBC2表达缺失(2/30),NTNBC组中21例DBC2表达缺失(21/50);TNBC组中19例DBC2表达缺失(19/38),其表达缺失率高于NTNBC组和正常乳腺组。结论 TNBC中DBC2表达明显缺失,其与肿瘤的增殖和高侵袭性相关,有望成为TNBC靶向治疗的潜在靶点。     

乳腺癌中雄激素受体的作用及其研究进展

乳腺癌是一类异质性肿瘤,其不同类型对治疗方案的选择和反应不尽相同。三阴型乳腺癌(triple negative breast cancer,TNBC)是一组ER、PR、HER-2均阴性的乳腺癌亚型,TNBC因缺乏受体的表达不能采用靶向治疗,而且常规的化疗效果也不佳,因此相较于其它类型的乳腺癌,TNBC的临床预后最差。雄激素受体(androgen receptor,AR)在TNBC中有一定的表达,虽然其表达与TNBC预后关系存在争议,但已有大量的体、内外试验证明AR抑制剂在阻断TNBC肿瘤细胞增殖时显示的有效性,尤其是在高表达AR的腺腔雄激素受体亚型中,这些研究都提示AR可能作为TNBC潜在的治疗靶位。     

维生素D通过下调谷氨酰胺合成酶抑制乳腺癌细胞增殖

目的 探究维生素D对非三阴性乳腺癌(non-triple negative breast cancer, Non-TNBC)和TNBC癌细胞增殖的影响及分子机制。方法 收集TNBC和Non-TNBC患者乳腺组织,原代培养TNBC和Non-TNBC患者乳腺细胞;免疫荧光检测乳腺细胞雌激素受体(ER)、孕激素受体(PR)和HER2蛋白表达;免疫荧光检测Non-TNBC和TNBC乳腺癌组织和乳腺细胞中VDR蛋白表达;CCK-8检测细胞活力变化;流式细胞术检测细胞增殖和细胞周期的变化;光学比色法检测细胞谷氨酰胺合成酶(glutamine synthetase, GS)活力的变化;ELISA检测细胞培养上清和胞内谷氨酰胺的水平;Western blot检测细胞GS和VDR蛋白表达的变化;CHIP-PCR检测VDR对GS的转录调控。结果 TNBC患者外周血中维生素D水平和癌组织VDR蛋白表达明显低于Non-TNBC患者(P<0.05)。相比于原代Non-TNBC乳腺癌细胞,原代TNBC患者乳腺癌细胞低表达雌激素受体(ER)、孕激素受体(PR)和HER2蛋白表达;TNBC乳腺癌细胞VDR表达水...     

p53突变在三阴性乳腺癌转移中的作用及机制

三阴性[雌激素（estrogen receptor,ER）、孕激素受体（progesterone receptor,PR）与人表皮生长因子受体-2（human epidermal growth factor receptor 2,HER-2）均为阴性]乳腺癌（triple negative breast cancer,TNBC）是一个具有特殊生物学行为及临床特征的乳腺癌亚型,而转移是其发病和致死的最主要原因。最近的研究表明,在TNBC中,高频率的p53突变能使p63转录活性丧失,此外,Shar p1作为p53突变/p63调节的主要基因之一,它抑制乳腺癌转移的功能亦丧失,而Shar p1之所以能抑制TNBC的浸润性转移,是因为Sharp1是促进缺氧诱导因子（hypoxia-inducible factor,HIF）降解以及减弱HIF诱导癌细胞恶变的重要因子,从而促进TNBC的转移。所以本文通过在中国知网、Pubmed和Highw ire上检索并研究近100篇文献的基础上,就p53突变通过p63/Shar p1/HIF信号通路促进TNBC转移的作用及机制做一综述。     

三阴型乳腺癌分子分型的新进展

三阴型乳腺癌(triple negative breast cancer,TNBC)中ER、PR和HER-2均阴性,具有高侵袭性、易复发转移、预后差等特点。目前,TNBC治疗效果欠佳,亟需进一步精准分型和开发新型肿瘤标志物。该文现就TNBC的分子分型进展作一综述。     

肿瘤相关巨噬细胞在三阴性乳腺癌中的研究进展

三阴性乳腺癌（TNBC）是恶性程度较高的乳腺癌亚型之一,高发于年轻女性,常见转移且预后较差。目前TNBC治疗多以化疗为主。近年研究发现,肿瘤相关巨噬细胞（TAMs）在TNBC发生发展、治疗评价中发挥重要作用。基于TAMs的治疗与预后评价策略已成为TNBC研究热点。本文就TAMs在TNBC发生进展及治疗评估中的作用进行概述。     

三阴性乳腺癌的靶向治疗

三阴性乳腺癌是一类异质性肿瘤,具有复发早、高侵袭及预后差的特点.三阴性乳腺癌的内分泌和HER2靶向治疗效果甚微.目前,三阴性乳腺癌的治疗以化疗为主,疗效也不佳.然而,随着三阴性乳腺癌的分子分型和肿瘤分子生物学研究,靶向研究在TNBC的治疗中取得了很大的进展.文章就TNBC的分子分型和靶向治疗的最新研究作一综述.     

Nucleolin overexpression in breast cancer cell sub-populations with different stem-like phenotype enables targeted intracellular delivery of synergistic drug combination

Breast cancer stem cells (CSC) are thought responsible for tumor growth and relapse, metastization and active evasion to standard chemotherapy. The recognition that CSC may originate from non-stem cancer cells (non-SCC) through plastic epithelial-to-mesenchymal transition turned these into relevant cell targets. Of crucial importance for successful therapeutic intervention is the identification of surface receptors overexpressed in both CSC and non-SCC. Cell surface nucleolin has been described as overexpressed in cancer cells as well as a tumor angiogenic marker. Herein we have addressed the questions on whether nucleolin was a common receptor among breast CSC and non-SCC and whether it could be exploited for targeting purposes.Liposomes functionalized with the nucleolin-binding F3 peptide, targeted simultaneously, nucleolin-overexpressing putative breast CSC and non-SCC, which was paralleled by OCT4 and NANOG mRNA levels in cells from triple negative breast cancer (TNBC) origin. In murine embryonic stem cells, both nucleolin mRNA levels and F3 peptide-targeted liposomes cellular association were dependent on the stemness status. An in vivo tumorigenic assay suggested that surface nucleolin overexpression per se, could be associated with the identification of highly tumorigenic TNBC cells. This proposed link between nucleolin expression and the stem-like phenotype in TNBC, enabled 100% cell death mediated by F3 peptide-targeted synergistic drug combination, suggesting the potential to abrogate the plasticity and adaptability associated with CSC and non-SCC.Ultimately, nucleolin-specific therapeutic tools capable of simultaneous debulk multiple cellular compartments of the tumor microenvironment may pave the way towards a specific treatment for TNBC patient care.     

SRT1720, a potential sensitizer for radiotherapy and cytotoxicity effects of NVB-BEZ235 in metastatic breast cancer cells

Background

Chemo-radio therapy (CRT) resistance is a main barrier in treating the triple negative breast cancer (TNBC). The success of conventional treatment may be ameliorated by elevating the responsiveness of the cancer cells to CRT. NVP-BEZ235 as a PI3K/AKT/mTOR dual inhibitor has been shown promising results in treating breast cancer cells. However, potential radiation-sensitizing effect of NVP-BEZ235 in TNBC remained unclear. In addition, SIRT-1 activation state and environmental cytokine were identified as being responsible for cancer cells responses to CRT. Herein, we investigate the role of interleukin 6 (IL-6) as a tumor environmental cytokine and SIRT1 in the effectiveness of NVP-BEZ235 plus radiotherapy.

Overexpression of CD85j in TNBC patients inhibits Cetuximab‐mediated NK‐cell ADCC but can be restored with CD85j functional blockade

Clinical studies suggest that triple negative breast cancer (TNBC) patients with epidermal growth factor receptor (EGFR)‐expressing tumors could benefit from therapy with Cetuximab, which targets EGFR. NK cells are the primary effectors of antibody (Ab)‐dependent cell‐mediated cytotoxicity (ADCC) and thus play a role in Ab‐based therapies. We have previously described diminished levels of Cetuximab‐mediated ADCC in vitro in patients with advanced breast cancer. Here, we investigated the potential causes of this NK‐cell functional deficiency. We characterized NK‐cell activating/inhibitory receptors in the peripheral blood of breast cancer patients and found CD85j inhibitory receptor overexpression. The capacity of NK cells to perform Cetuximab‐triggered ADCC against TNBC cells correlated inversely with CD85j expression, even in the presence of the stimulatory cytokines IL‐2 or IL‐15. Hence, patients expressing high levels of CD85j had an impaired ability to lyse TNBC cells in the presence of Cetuximab. We also found that CD85j overexpression was associated with HLA‐I and soluble HLA‐G expression by tumors. A CD85j functional blockade with a CD85j antagonist Ab restored ADCC levels in breast cancer patients and reverted this negative effect. Our data suggest that strategies that overcome the hurdles of immune activation could improve Cetuximab clinical efficacy.     

The expression and clinical significance of ribophorin II (RPN2) in human breast cancer

Ribophorin II (RPN2), part of the N‐oligosaccharyltransferase complex, is highly expressed in breast cancer stem cells and is associated with tumor metastasis through interaction with mutant p53. The clinicopathological implication of RPN2 expression is undetermined. We examined immunohistochemically the expression levels of RPN2 and p53 in primary breast cancer tissues surgically resected from 218 patients. The correlations of RPN2 expression with the intrinsic subtype defined by hormone receptors (HRs) and HER2, clinicopathological parameters, p53 expression, and patients’ clinical outcomes were examined. RPN2 was positive in 139 (64%), and the incidence of RPN2 expression was higher in the triple‐negative breast cancer (TNBC) (HR‐/HER2‐) (65%) and HER2‐enriched (HR‐/HER2+) subtype (95%) than in the luminal A‐like (HR+/HER2‐) subtype (58%) (P = 0.0009). RPN2 expression was also correlated with p53 nuclear accumulation (P = 0.04). The RPN2‐positive/p53‐positive patient group showed significantly poorer prognosis than the RPN2‐negative group for disease‐free survival (P = 0.05) and for overall survival (P = 0.02). By multivariate analyses, the combination of RPN2 and p53 was not an independent prognostic factor. RPN2 expression was correlated with clinically aggressive features of breast cancer. These data support the further clinical application of anti‐RPN2 therapy and the development of personalized medicine.     

Synaptopodin‐2 suppresses metastasis of triple‐negative breast cancer via inhibition of YAP/TAZ activity

Triple‐negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer, with a high incidence of distant metastasis; however, the underlying mechanism for this frequent recurrence remains unclear. Herein, we show that synaptopodin‐2 (SYNPO2), a putative tumour suppressor in aggressive cancer, is frequently downregulated in TNBC by methylation of the promoter of SYNPO2. Low expression levels of SYNPO2 correlated significantly with 5‐year metastatic relapse, and predicted poorer prognosis in breast cancer patients. Reintroduction of SYNPO2 inhibited the invasion and spontaneous metastasis of TNBC cells in vivo. Strikingly, downregulation of SYNPO2 is essential for the maintenance of stem cell‐like properties in TNBC cells, leading to efficient distant colonization and metastasis outgrowth. Moreover, we demonstrate that SYNPO2 inhibits the activities of YAP and TAZ by stabilizing LATS2 protein, and transduction of YAP‐S127A abrogates the repressive role of SYNPO2 in metastasis. Finally, immunohistochemical (IHC) analysis of breast cancer patient specimens indicated that the SYNPO2–LATS2–YAP axis is clinically relevant. These findings uncover a suppressive role of SYNPO2 in TNBC metastasis via inhibition of YAP/TAZ, and suggest that SYNPO2 might provide a potential prognosis marker and novel therapeutic strategy. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Down-regulation of BRMS1 by DNA hypermethylation and its association with metastatic progression in triple-negative breast cancer

Breast cancer metastasis suppressor 1 (BRMS1) is a metastasis suppressor gene in several solid tumors. However, the expression and function of BRMS1 in triple-negative breast cancer (TNBC) have not been reported. In this study, we found that BRMS1 was down-regulation in breast cancer cell lines and primary TNBC, while decreased expression of BRMS1 mRNA was significantly associated with lymph node metastasis. And this down-regulation was found to be in accordance with aberrant methylation of the gene. Hypermethylation of the gene was observed in 53.4% (62/116) of the TNBC primary breast carcinomas, while it was found in only 24.1% (28/116) of the corresponding nonmalignant tissues. In addition, BRMS1 expression was restored in MDA-MB-231 after treatment with the demethylating agent, 5-aza-2-deoxycytidine (5-Aza-dC), and demethylation of the highly metastatic cells MDA-MB-231 induced invasion suppression of the cells. Furthermore, the suppression of BRMS1 by siRNA transfection enhanced cancer cells invasion. Collectively, our results suggest that the aberrant methylation of BRMS1 frequently occurs in the down-regulation of BRMS1 in TNBC and that it may play a role in the metastasis of breast cancer.