PI3K/Akt信号通路在乳腺癌内分泌治疗耐药中的作用及对策

乳腺癌是女性最常见的肿瘤,大约75％的乳腺癌表达雌激素受体和/或孕激素受体.激素受体阳性的转移性乳腺癌患者通常采用内分泌治疗,然而由于内分泌治疗耐药的产生,其应用受到了限制.近年来发现,PI3K/Akt(丝氨酸/苏氨酸激酶)信号通路在乳腺癌的发展中发挥着重要作用.本文对PI3K/Akt信号通路在乳腺癌内分泌治疗耐药中的作用进行了综述,以期为雌激素受体阳性乳腺癌治疗提供新对策.     

小分子酪氨酸激酶抑制剂耐药机制

表皮生长因子受体(epidermal growth factor receptor,EGFR)通路异常在肿瘤发生、发展过程中起到非常重要的作用,特异性抑制该通路的小分子受体酪氨酸激酶抑制剂在肿瘤治疗上取得了显著的效果,但是该药在临床上已经出现耐药现象,现将有关EGFR基因突变、EGFR旁路信号通路的激活、下游信号分子的结构性活化3个方面对EGFR抑制剂耐药机制的研究进展进行综述.     

癌症和艾滋病研究动态

近年来，癌症和艾滋病的基础研究以及实验室和临床相结合的转化医学研究不断向前发展，笔者就近年来的一些研究情况加以总结供读者参考。
　　1我国相关研究的情况
　　据2011年5月16日国际权威学术期刊《自然医学》在线发表，我国研究人员在乳腺癌内分泌治疗的耐药机制研究中获重要成果。由于多数乳腺癌是雌激素依赖的恶性肿瘤，因此内分泌治疗成为乳腺癌患者得以长期生存的重要手段之一。其中他莫西芬是目前应用最广泛的乳腺癌内分泌治疗药物，通过与体内雌激素竞争性结合雌激素受体而抑制肿瘤细胞的生长。但是，乳腺癌治疗中存在的耐药问题大大影响了他莫西芬的临床疗效，因此研究耐药机制已成为乳腺癌治疗的一个亟待解决的重要科学问题。针对这一世界性难题，我国研究人员从多个层次研究发现炎症调控分子CUEDC2在乳腺癌细胞中过量表达导致了乳腺癌患者对内分泌治疗产生耐药，并深入揭示了 CUEDC2诱发耐药的全新分子机制。这一发现为克服乳腺癌耐药提供了原创性的药物新靶点和治疗新思路，对指导乳腺癌的临床治疗具有重要意义。     

表皮生长因子受体与雌,孕激素受体在乳腺癌组织中的表达及相互关系

本文应用碘标记的表皮生长因子，用分步离心提取部细胞膜蛋白，以标准的ＥＧＦ作竞争剂，采取放射标记结合法测定了４０例乳腺癌组织中的表皮生长因子受体水平，同时采用葡聚糖活性碳分析法测定了乳腺癌组织中的雌激素受体，孕激素受体以探讨ＥＧＦＲ表达与ＥＲ，ＰＲ在乳腺癌组织中的生物学行为及相互关系。     

乳腺癌MDA-231细胞中IL-8与表皮生长因子受体信号通路的关系

目的 探讨IL-8对乳腺癌细胞增殖和侵袭的影响以及IL-8信号通路与表皮生长因子受体(EGFR)信号通路之间的关系.方法 采用ELISA方法检测乳腺癌MDA-231细胞IL-8的分泌及rhEGF、anti-EGFR对IL-8分泌的影响;免疫细胞化学方法检测其膜受体CXCR1和CXCR2的表达;MTT和matrigel invasion(基质凝胶侵袭)方法分析rhIL-8及anti-IL-8对癌细胞增殖和侵袭的影响;Western blot分析rhlL-8及anti-IL-8对EGFR活化的影响.结果 乳腺癌细胞可分泌大量IL-8,其细胞膜表面表达CXCR1和CXCR2两种受体.rhlL-8及其中和抗体对乳腺癌细胞的增殖无明显影响,但可影响其侵袭能力:rhIL-8可提高癌细胞的侵袭活性(P＜0.05),其中和抗体则对癌细胞的侵袭有抑制作用(P＜0.05).rhEGF及anti-EGFR均明显抑制了MDA-231细胞IL-8的分泌(P＜0.05,P＜0.01);未发现rhIL-8对EGFR的酪氨酸磷酸化有任何影响,相反anti-IL-8却诱导了EGFR活化.结论 IL-8不是乳腺癌自分泌的促细胞生长因子,IL-8主要通过促进癌细胞的侵袭而影响肿瘤的发展.乳腺癌中G蛋白耦联受体(GPCR)介导的IL-8信号通路与EGFR信号通路之间并无cross-talk,而是竞争抑制的关系.     

选择性雌激素受体调节剂耐药受体机制研究进展

在乳腺癌内分泌治疗中 ,SERM耐药或治疗失效病例的进一步治疗为临床一大问题 ,近年来的研究发现雌激素受体蛋白的变异 ,以及受体激活过程中各种辅助蛋白的结构与功能异常 ,都可能是 SERM耐药的重要机制。现将 SERM耐药受体机制的研究进展作一综述 ,为临床 SERM耐药病例的治疗或 SERM耐药的逆转研究提供帮助。     

雌激素及其受体与自身免疫性疾病

自身免疫性疾病有明显的性别差异，女性的发病率显著高于男性，表明雌激素影响这类疾病的发生。雌激素及其代谢产物水平、雌激素受体基因多态性、雌激素受体介导的信号通路等方面与自身免疫性疾病密切相关，雌激素及其受体在自身免疫性疾病治疗中发挥重要作用。     

细胞自噬与乳腺癌他莫昔芬耐药相关性的研究进展

乳腺癌是威胁妇女健康的主要恶性肿瘤之一。雌激素受体(Estrogen receptor,ER)阳性(ER+)和/或孕激素受体(Progestrone receptor,PR)阳性(PR+)约占所有乳腺癌的75%,内分泌治疗是ER+和/或PR+乳腺癌的有效治疗方式之一。他莫昔芬(Tamoxifen,TAM)为抗雌激素药物,普遍应用于ER+的乳腺癌患者治疗,延长患者生存时间。但他莫昔芬耐药导致的ER+乳腺癌复发和死亡威胁着患者的预后。细胞自噬是细胞通过降解自身物质使细胞存活的一种自我保护机制,主要作用为清除细胞内错误折叠蛋白或损伤细胞器,维持细胞稳态。本文综述细胞自噬与乳腺癌他莫昔芬耐药相关性的研究进展,为解决乳腺癌他莫昔芬耐药提供新的策略。     

KDM5B基因在乳腺癌中的表达及其临床意义

目的:研究KDM5B基因在乳腺癌组织中的表达情况,并探讨其表达差异与患者临床病理资料和预后的关系。方法:从肿瘤基因组图谱(TCGA)数据库中收集113例正常乳腺组织和1 090例乳腺癌数据集,下载KDM5B mRNA表达谱资料;收集中山大学附属第三医院甲乳外科2015年～2016年乳腺癌切除标本共90例,采用real-time PCR的方法检测乳腺癌及其癌旁组织中KDM5B mRNA的表达量,取中位数分为高表达组与低表达组,分析其与临床资料及病例特征的关系;利用Kaplan-Meier plotter分析KDM5B mRNA表达与乳腺癌患者预后的相关性。结果:KDM5B在乳腺癌中的表达均显著高于正常乳腺组织(P 0. 01)。在TCGA的乳腺癌数据中,KDM5B的表达与人表皮生长因子受体2(HER2)、雌激素受体(ER)、年龄、病理组织类型及淋巴结转移显著相关(P 0. 01),与孕激素受体(PR)、绝经及远处转移无显著相关。在我们收集的乳腺癌样本中,KDM5B的表达与HER2、年龄及淋巴结转移显著相关(P 0. 05),而与ER、PR、绝经、病理组织类型和远处转移无显著相关。KDM5B表达越高,乳腺癌患者总生存时间(HR=1. 39,P=0. 005)和无病生存时间(HR=1. 32,P 0. 001)越短。结论:在乳腺癌组织中KDM5B高表达,且与患者的预后相关; KDM5B的表达与乳腺癌患者HER2表达、年龄和淋巴结转移显著相关。     

选择性表皮生长因子受体酪氨酸激酶抑制剂--ZD1839对NK和LAK细胞毒作用的影响

表皮生长因子受体(epidermal growth factor receptor，EGF受体)在某些实体瘤表达增加，包括非小细胞肺癌(non．smallcelllungcancer，NSCLC)、乳腺癌、头颈部肿瘤和胃癌等，EGF受体表达与肿瘤的进展、治疗抵抗有关；它的信号转导通路的活化与肿瘤细胞增殖、血管生成、抑制肿瘤细胞凋亡和肿瘤转移有关，因此，EGF受体成为抗癌治疗的靶向分     

血清外泌体miR-575与ER阳性乳腺癌患者他莫昔芬辅助治疗预后的相关性研究

目的研究血清外泌体miR-575水平与雌激素受体(ER)阳性乳腺癌患者他莫昔芬辅助内分泌治疗预后的相关性。方法通过生物信息学分析miR-575表达水平与乳腺癌患者总体生存率的关系。采集接受他莫昔芬辅助内分泌治疗的162例ER阳性乳腺癌患者的血液样本作为观察组,另外收集165例非癌志愿者的血液样本作为对照组,以实时荧光定量PCR法检测血清外泌体miR-575表达水平。观察组患者至少随访5年,根据患者对他莫昔芬的耐药情况将其分为抵抗组和敏感组,分析血清外泌体miR-575表达水平与术后疾病进展的关系。采用单因素和多因素Cox回归分析影响ER阳性乳腺癌患者他莫昔芬治疗预后的临床因素,并绘制受试者工作特征(ROC)曲线,计算曲线下面积(AUC)。结果生物信息学结果显示,miR-575在乳腺癌组织中的表达水平明显高于正常乳腺组织(P<0.001);且在ER阳性患者中,miR-575表达水平升高与Nottingham病理学分级较高以及预后不良有关(P<0.05)。观察组患者血清外泌体miR-575相对表达水平高于对照组1.834(1.168,2.519)vs.1.003(0.901,1.217),Z=-8.871,P<0.001;观察组患者血清外泌体与乳腺癌组织miR-575相对表达水平呈正相关(rs=0.726,P<0.001)。随访5年,110例患者对他莫昔芬耐药(抵抗组),52例对他莫昔芬敏感(敏感组)。抵抗组血清外泌体miR-575相对表达水平明显高于敏感组2.097(1.700,3.163)vs.1.168(0.947,1.524),Z=-7.164,P<0.001。Kaplan-Meier曲线显示,血清外泌体miR-575高表达组患者中位疾病进展时间短于低表达组(P<0.001)。Cox回归分析和ROC曲线结果显示,血清外泌体miR-575高表达是ER阳性乳腺癌患者接受他莫昔芬辅助内分泌治疗预后不良的独立危险因素(P<0.05),预测5年疾病进展的AUC为0.850(95%CI0.789~0.910)。结论血清外泌体miR-575表达水平较高预示着ER阳性乳腺癌患者接受他莫昔芬辅助内分泌治疗预后不良,有望成为预测他莫昔芬敏感性的一个重要参考指标。     

Amplified in breast cancer 1 expression in breast cancer

Aims: The amplified in breast cancer 1 (AIB1), steroid receptor co‐activator family member, acts as an oestrogen receptor (ER) co‐activator. Acting with HER‐2, it is thought to play a role in endocrine resistance by facilitating ER–growth factor crosstalk. The aim was to analyse AIB1 expression by immunohistochemistry and study its correlations with other prognostic variables in breast cancer and its effect on survival. Methods: A tissue microarray comprising tumours from 438 patients with 15.4 years’ median follow‐up was used. Interpretable AIB1 expression obtained in 395 patients was analysed along with other prognostic factors in breast cancer. Results: AIB1 expression scores ranged from 0 to 30; positive AIB1 expression (score > 14) was seen in 146/395 breast cancers; it correlated negatively with ER (P = 0.003) and progesterone receptor (PR) (P = 0.007), and positively with HER‐2 (P = 0.005) and tumour grade (P = 0.014). It did not correlate with nodal status (P = 0.437). Among ER+ patients, AIB1 expression showed a trend towards loss of PR expression (29% versus 20%; P = 0.14). AIB1 did not predict survival on univariate or multivariate analysis. Conclusions: AIB1 expression correlates with HER‐2 expression in breast cancer and shows a trend of association with loss of PR expression in ER+ tumours. Our study supports the postulated role of AIB1 in ER–growth factor interactions.     

Progress in endocrine approaches to the treatment and prevention of breast cancer

Tamoxifen had been the only available hormonal option for the systemic treatment for breast cancer from 1973 to 2000. Enormous efforts have led to the development of potent and selective third generation aromatase inhibitors including anastrozole, letrozole and exemestane. Due to their superior efficacy to tamoxifen, aromatase inhibitors are presently approved as first line agents for the treatment of advanced estrogen receptor (ER) positive breast cancer and adjuvant therapy in early ER positive early breast cancer in postmenopausal women. Selective ER Modulators (SERMS), tamoxifen and raloxifene are the only agents presently used in breast cancer prevention in high risk women and their use has increased substantially over the last decade. Third generations SERMS, lasofoxifene and bazedoxifene have shown significant reduction in bone loss compared to placebo in postmenopausal women and are currently approved in the European Union for the treatment of postmenopausal osteoporosis. This review outlines the current strategies employed in the use of endocrine therapy in the management and prevention of breast cancer.     

乳腺癌易感基因1的表达与乳腺癌亚型关系的实验研究

目的 探讨乳腺癌易基因1（BRCA1）的表达与乳腺癌分子亚型的关系.方法 运用免疫组化法检测乳腺癌组织中BRCA1的表达与雌二醇受体（ER）和人表皮生长因子受体-2（Her-2）的关系,分析BRCA1的表达在乳腺癌各亚型中的意义.结果 ER阳性和阴性时,BRCA1的阳性率分别为40.2％和60.0％,表明BRCA1表达与ER有关（P＜0.05）,与Her-2无关（P＞0.05）.在乳腺癌各分子亚型中,Luminal B型和Her-2过表达型的BRCA1阳性率（66.7％和70.0％）与Basal-like型的BRCA1阳性率（75.0％）差别无统计学意义（P＞0.05）;Luminal A型的BRCA1阳性率（23.7％）低于Basal-like型的BRCA1阳性率（75.0％）,差别具有统计学意义（P＜0.05）.结论 BRCA1在Luminal B型、Her-2过表达型和Basal-like型乳腺癌中表达较高,在Luminal A型乳腺癌中表达不高,提示BRCA1可成为治疗乳腺癌的重要靶点.     

Oestrogen receptor and epidermal growth factor receptor expression in male breast carcinoma.

Male breast carcinomas are probably hormone-dependent, but receptor studies are few because this is a relatively rare tumour. We have studied 21 cases of male breast carcinoma immunohistochemically for oestrogen receptor (ER) and epidermal growth factor receptor (EGFR) expression employing the antibodies ER-ICA and 12E on formalin-fixed, paraffin-embedded material. In our series, 86 per cent of male breast cancers were ER-positive and 76 per cent were EGFR-positive. Male breast carcinomas do not exhibit the inverse correlation between ER and EGFR expression that characterizes female breast carcinomas. Owing to the limitations of a small series, we were unable to comment on the relationship between ER and EGFR expression and patient survival. However, the relatively high incidence of ER expression may provide a growth advantage for this tumour in a male environment characterized by low levels of oestrogen. In addition, high EGFR expression may also contribute to a poor prognosis independent of ER status.     

Prognostic value of pathologic complete response and the alteration of breast cancer immunohistochemical biomarkers after neoadjuvant chemotherapy

Neoadjuvant chemotherapy(NCT) has become the standard treatment for breast cancer. The information about the tumor’s sensitivity to chemotherapy and prognostic significance based on response to therapy can be provided after individualized neoadjuvant treatment. The biomarkers are key factors in the decision-making process regarding treatment as well as important prognostic indicators. Studies have shown that patients who achieve pathological complete response(pCR) after NCT have a better prognosis. For patients who do not achieve pCR, the pathological characteristics of the residual tumor can make an effect on the survival. Furthermore, the immunohistochemical (IHC) markers of the residual diseases after primary systemic therapy might be different from the primary tumor. Estrogen receptor (ER), progesterone receptor (PR), and Ki67 can usually change after NCT, while human epidermal growth factor receptor 2(HER2) seems to be more stable. The relationship between changes in breast cancer molecular biomarkers and the prognosis after neoadjuvant therapy is not yet clear. The article will make a review about it.