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。     

三阴性乳腺癌干细胞微球体的治疗

三阴性乳腺癌(TNBC)是指雌激素受体(ER)、孕激素受体(PR)及人类表皮生长因子受体2 (HER-2)均为阴性的乳腺癌。TNBC恶性程度高,
侵袭性强,易远处转移,预后差,对内分泌治疗及靶向治疗的效果均欠佳,是临床治疗的难点。近几年研究发现,三阴性乳腺癌的发生、发展
很可能与其中的乳腺癌干细胞有关,乳腺癌干细胞微球体培养是一种收集干细胞的方法,被广泛用于三阴性乳腺癌的干细胞研究。     

乳腺癌分子标志和分子分型

乳腺癌是生物学高度异质性的肿瘤,雌激素受体(estrogen recept,ER)、孕激素受体(progester-one recept,PR)、人表皮生长因子受体2(human epidermal growth factor 2,HER-2)是目前预测预后和指导治疗重要的分子标志。随着分子生物学技术的不断进步,可以根据ER、PR、HER-2表达状态和细胞形态学可以将乳腺癌大致分成4至5个亚群,即Luminal(ER /PR )、HER-2 (ER-,PR-,HER-2 )、Basal-like(ER-,PR-,HER-2-)和Normal-like等,它们在临床治疗反应和生存方面截然不同。因此,对乳腺癌进行分子标志检测或分子分型有利于判断患者的临床预后和指导临床治疗。     

三组HER-2双色探针不同杂交时间下检测乳腺癌临床样本

正人类表皮生长因子受体2(human epidermal growth factor receptor 2,HER-2)基因编码一种跨膜酪氨酸激酶受体,通过细胞间信号传导调节细胞生长、分化和增殖[1-3]。目前曲妥珠单抗(Trastuzumab)、拉帕替尼(Lapatinib)靶向治疗HER-2阳性的乳腺癌患者,因此正确快速检测、评定HER-2表达和基因扩增状态对乳腺癌临床治疗和预后判断至关重要。传     

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。     

基于数字乳腺三维断层摄影技术的乳腺癌分子亚型特征

目的:研究乳腺癌各分子亚型在数字乳腺三维断层技术(DBT)表现的特征。方法:回顾分析2013年5月~2014年10月在福建医科大学附属第二医院接受手术同时有完整的病理及免疫组化资料的乳腺癌病人78例,根据雌激素受体(ER)、孕酮受体(PR)、人表皮生长因子受体(HER-2)的表达和Ki-67将乳腺癌分为Luminal A型、Luminal B型、三阴性型和HER-2的过表达型,研究不同分子亚型乳腺癌DBT影像表现特征、临床与病理表现特征。结果:各个分子亚型是否存在肿块无统计学差异,HER-2过表达型较Luminal A型、Luminal B型肿块大,与Luminal B型比较有统计学意义,与Luminal A型比较无统计学意义;钙化分数:HER-2过表达型较Luminal A型和Luminal B型显著增高,差异有统计学意义;不同分子亚型在乳腺BI-RADS分类差异无统计学意义。Luminal B型乳腺癌淋巴结转移率明显高于其它分子分型。结论:基于乳腺三维断层摄影技术,乳腺癌分子亚型具有一定特征性。     

血清HER-2DNA在乳腺癌中的诊断价值及临床意义

目的检测乳腺癌患者血清人类表皮生长因子受体2(human epidermal growth factor receptor 2,HER-2)DNA的水平,探讨其诊断价值及临床意义。方法收集乳腺癌血清标本92例、乳腺良性病变血清标本37例、健康对照血清标本53例,利用实时荧光定量PCR方法检测血清HER-2 DNA水平,并分析血清HER-2 DNA与乳腺癌临床病理特征的关系及其对乳腺癌的诊断效能。结果乳腺癌组血清HER-2DNA水平[3 088.2(1 681.4~5 592.2)copies/μl]明显高于乳腺良性病变组和健康对照组(P<0.05);肿瘤大小、有无淋巴转移及病理学分级和TNM分期的乳腺癌患者血清HER-2 DNA水平差异有显著性(P<0.05);以1 675.5 copies/μl为临界值,血清HER-2诊断乳腺癌的灵敏度为72.6%,特异性为73.1%。结论血清HER-2 DNA在乳腺癌患者中明显升高,并与乳腺癌的临床特征关系密切,有望成为乳腺癌诊断的实验室指标之一。     

微浸润及T1a期乳腺癌中HER-2(0)和(1+)的临床意义及预后分析

目的 探讨微浸润乳腺癌(microinvasive carcinoma)及T1a期乳腺癌中HER-2(0)和(1+)的临床意义及预后分析。方法 收集109例微浸润乳腺癌及154例T1a期乳腺癌的临床资料，采用免疫组化检测重新判读HER-2等免疫组化指标及肿瘤浸润淋巴细胞(tumor infiltrating lymphocytes, TILs),分析HER-2(0)或(1+)对微浸润乳腺癌及T1a期乳腺癌患者淋巴结转移及预后的影响。结果 HER-2(0)者126例(47.9%),HER-2(1+)者137例(52.1%)。其中HER-2(0)组中HR阳性112例(88.9%),三阴型乳腺癌(triple negative breast cancer, TNBC)14例(11.1%);HER-2(1+)组中HR阳性125例(91.2%),TNBC 12例(8.8%)。HER-2(0)组与HER-2(1+)组相比，患者年龄、浸润灶个数、浸润灶大小、组织学分级、ER、PR、Ki-67、TILs等差异均无统计学意义(P均>0.05)。多元Logistic分析结果显示，HER-2状态是影响...     

乳腺MRI预测浸润性导管癌分子亚型的临床价值

目的:探讨乳腺浸润性导管癌磁共振成像(Magnetic resonance imaging,MRI)表现与乳腺癌分子分型的相关性.方法:将327例单发浸润性导管癌分为管腔上皮A型(Luminal A)、管腔上皮B型(Luminal B)、人类表皮生长因子受体2(Human epidermal growth factor receptor-2,HER-2)过表达(激素受体(Hormone receptor,HR)阳性)、HER-2过表达HR阴性、三阴型,比较各型间的影像学特征.结果:Luminal A型57例、Luminal B型124例、HER-2过表达(HR阳性)55例、HER-2过表达(HR阴性)49例、三阴型42例.病灶早期强化率及达峰时间与分子分型间无明显差异(P>0.05).Luminal B型病灶比Luminal A型、HER-2过表达(HR阴性)、三阴型病灶的表观弥散系数(Apparent diffusion coefficient,ADC)值低(P<0.0.5).Luminal A型比Luminal B型、HER-2过表达(HR阳性)病灶的ADC值高(P<0.0.5).结论:MRI影像学特征可以用于初步预测乳腺浸润性导管癌的病理分子分型.     

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.     

Insulin receptor is implicated in triple-negative breast cancer by decreasing cell mobility

Triple-negative breast cancer (TNBC) has a poor prognosis and typically earlier onset of metastasis in comparison with other breast cancer subtypes. It has been reported that insulin receptor (INSR) is downregulated in TNBC, however, its clinical significance and functions in TNBC remain to be elucidated. In this study, we found that INSR expression was significantly downregulated in TNBC, and overexpression of INSR suppressed cell migration and invasion in TNBC. In addition, the survival rate of breast cancer patients with low INSR expression was lower than that of patients with high INSR expression. INSR expression was significantly correlated with lymph node metastasis, clinical tumor stages, ER status, PR status, and the proliferation index Ki-67 expression. In summary, our study suggests that INSR may serve as a biomarker for breast cancer prognosis and it may be a potential target for TNBC treatment.     

Tumor-infiltrating lymphocytes and PD-L1 in breast cancer (and,what happened to medullary carcinoma?)

Tumor-infiltrating lymphocytes (TILs) and PD-L1 have emerged as important immune biomarkers in breast cancer, particularly triple negative breast carcinomas (TNBC) and human epidermal growth factor-2 positive (HER-2⁺) breast carcinomas. These components of the tumor immune microenvironment can be harnessed or targeted with immunotherapy, which represents a significant advancement in the management of TNBC. TILs are a prognostic biomarker in breast cancer, and this recognition has led to reclassification of medullary carcinoma (which were TILs rich by definition) as a pattern of invasive ductal carcinoma (no special type) rather than a distinct histologic type. PD-L1 is a predictive biomarker in TNBC, and two different PD-L1 assays have been approved as companion diagnostics for immune checkpoint inhibition in TNBC. This review will cover the roles of TILs and PD-L1 testing in breast cancer, both of which provide important clinical information to guide patient prognosis and therapy. This is a rapidly evolving and exciting field with significant implications for patient care.     

Yes-associated protein (YAP) is differentially expressed in tumor and stroma according to the molecular subtype of breast cancer

In this study, we aimed to clarify the expression profiles of Yes-associated protein (YAP) and phosphorylated YAP (pYAP) protein and to verify the clinical implication of the expression of YAP protein in human breast cancer. We selected 678 cases of formalin-fixed paraffin-embedded (FFPE) breast cancer tissue to construct tissue microarray (TMA) blocks. We performed immunohistochemical staining of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth receptor-2 (HER-2) and Ki-67 and fluorescent in situ hybridization (FISH) assay for HER-2 on the TMA sections and divided breast cancers into molecular subtypes: luminal A, luminal B, HER-2, triple negative breast cancer (TNBC). Then, we examined YAP and pYAP expression status using immunohistochemical analysis according to the molecular subtypes of breast cancer. We found that HER-2 type breast cancer demonstrated elevated expression level in tumoral cytoplasmic YAP (P = 0.011) and pYAP (P = 0.049). Expressions of stromal YAP (P = 0.002) and pYAP (P < 0.001) were higher in luminal B and HER-2 type breast cancer but lower in TNBC. In univariate analysis, nuclear YAP expression of tumor cells was associated with shorter overall survival (OS) (P = 0.024). Cytoplasmic YAP expression of HER-2 type breast cancer cells negatively affected disease-free survival (DFS) (P = 0.034). In conclusion, we concluded that there was a significant difference in YAP and pYAP expression status according to molecular subtypes and tumoral and cellular components of breast cancers. Finally, we found that nuclear and cytoplasmic YAP expression could be a prognostic marker for breast cancer patients.     

Combination of thiazolidinedione and hydralazine suppresses proliferation and induces apoptosis by PPARγ up-expression in MDA-MB-231 cells

No proven targeted therapy is currently available for the treatment of triple-negative breast cancer (TNBC). Ligand activation of peroxisome-activated receptor (PPAR)γ induces antitumor effects in cancer but not obviously in TNBC. In TNBC cells, combined treatment with thiazolidinedione and demethylation drugs Hydralazine up-regulated protein and mRNA levels of PPARγ. Besides, the combination of two drugs promote antiproliferative and apoptotic effects in TNBC cells and decrease the proliferation index in the tumor xenografts. Taken together, our results suggest that multidrug regimens including a combination of Thiazolidinedione and Hydralazine may provide a therapeutic advantage in TNBC.     

GABRP基因在基底样三阴乳腺癌中的差异表达

目的:探索GABRP基因在基底样三阴乳腺癌(basal-like Triple negative breast cancer,BLTNBC)中的表达,为临床提供预后诊断分子标志物.方法:通过生物信息学分析比较GABRP基因的表达;采用定量PCR方法检测GABRP基因在乳腺癌细胞系及104例乳腺癌石蜡样本中的差异表达,并采用相关性分析、卡方检验及Fisher精确概率法分析GABRP基因与细胞增殖、淋巴结转移、ER及HER-2基因表达的相关性.结果:生物信息学分析和定量PCR结果显示GABRP基因在三阴性乳腺癌(triple negative breast cancer,TNBC)及BLTNBC中显著性高表达(p＜0.05);在non-TNBC,TNBC,BLTNBC中,其表达与细胞增殖、HER-2表达无明显相关性(P＞0.05),而在BLTNBC中与淋巴结转移状态有明显相关性(P＜0.05),在non-TNBC巾与ER表达有明显相关性(P＜0.05).结论:GABRP基因可作为BLTNBC的有潜力的预后诊断分子标志物.     

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...