FSIP1促进乳腺癌细胞迁移和侵袭并导致患者不良预后

目的 探讨乳腺癌组织中纤维鞘相互作用蛋白1(FSIP1)表达对乳腺癌细胞侵袭和迁移能力的影响及其与乳腺癌患者预后的关系,从而为乳腺癌的诊断和治疗提供一定的理论参考。方法 收集2004年1月—2018年12月于哈尔滨医科大学附属肿瘤医院确诊的404例乳腺癌患者的乳腺组织样本和病例资料,对收集的乳腺癌患者资料进行回顾性分析并采用Kaplan-Meier方法绘制生存曲线,采用免疫组织化学方法分析FSIP1在乳腺癌和癌旁组织中的表达情况,取乳腺癌细胞系MCF-7、MDA-MB-231、MDA-MB-435、SK-BR-3、T-47D及正常乳腺上皮细胞(HMECs)MCF-10A进行细胞培养,采用CRISPR/CAS9技术敲除乳腺癌细胞系MDA-MB-231和SK-BR-3中的FSIP1基因,通过Western blot实验检测各乳腺癌细胞系中FSIP1蛋白的表达情况并对FSIP1基因敲除结果进行检测,通过细胞迁移和侵袭实验评估FSIP1蛋白敲除对乳腺癌细胞迁移和侵袭能力的影响。结果 与正常乳腺上皮细胞(MCF-10A)相比,乳腺癌细胞系MCF-7、MDA-MB-231、MDA-MB-435、SK-BR-3、T-47D中FSIP1的表达水平均显著升高(P＜0.01);与癌旁乳腺组织相比,乳腺癌组织中FSIP1的表达水平显著升高(P＜0.01);生存分析结果显示,FSIP1表达水平较高的乳腺癌患者总生存期显著缩短(P＜0.001),且FSIP1的表达水平与乳腺癌患者的临床分期(P=0.006)及细胞增殖标记物Ki-67(P=0.0067)表达相关;迁移实验和侵袭实验结果显示,敲除FSIP1基因后乳腺癌细胞系MDA-MB-231和SK-BR-3的迁移和侵袭能力显著降低(P＜0.01)。结论 FSIP1在乳腺癌细胞中高表达能够增强其迁移和侵袭能力,并与患者预后不良相关。     

Expression and clinicopathological significance of FSIP1 in breast cancer

Aim

To investigate the clinicopathological significance of the expression of fibrous sheath interacting protein 1 (FSIP1) in breast cancer, serum samples, and wound fluid from patients with breast cancer.

Methods

Wound fluid and serum samples from female patients with primary breast cancer, recurrent and metastatic breast cancer, and benign tumors were analyzed for FSIP1 expression using ELISA. 286 paraffin-embedded surgical specimens from breast cancer patients with at least 5 years of follow-up were included for FSIP1 expression assay using immunohistochemistry.

Results

Expression of FSIP1 protein was significantly higher in breast cancer tissues compared to tumor-adjacent tissues (p = 0.001). Strong correlation was observed between FSIP1 expression and human epidermal growth factor receptor 2 (Her-2) or Ki67 expression in breast cancer (p = 0.027 and 0.002, respectively). Similarly, serum level of FSIP1 was higher in patients with recurrent and metastatic breast cancer compared to that of primary breast cancer (7, 713 ± 3, 065 vs. 4, 713 ± 3, 065 pg/ml, p = 0.003). Finally, patients with high FSIP1 expression showed a worse post-operative disease-specific survival (p = 0.024).

Conclusion

FSIP1 may play an important role in the tumorigenesis and invasion of breast cancer and is a potential biomarker for breast cancer diagnosis or prognosis.     

Tryptophanyl-tRNA Synthetase Sensitizes Hormone Receptor-Positive Breast Cancer to Docetaxel-Based Chemotherapy

PurposeA relatively low response to chemotherapy has been reported for hormone receptor (HR)-positive breast cancer. In this study, we investigated the role of tryptophanyl-transfer RNA synthetase (WARS) in the chemotherapeutic response of HR-positive breast cancer.MethodsPre-chemotherapeutic needle biopsy samples of 45 HR-positive breast cancer patients undergoing the same chemotherapeutic regimen were subjected to immunohistochemistry. To investigate the biological functions of WARS in HR-positive breast cancer, we conducted cell viability assay, flow cytometry analysis, caspase activity assay, Quantitative real-time polymerase chain reaction, and western blotting using WARS gene-modulated HR-positive breast cancer cells (T47D, ZR-75-1, and MCF7).ResultsWARS overexpression in HR-positive breast cancer patients showed a significant correlation with favorable chemotherapy response. Downregulation of WARS increased cell viability following docetaxel treatment in tumor cell lines. On the other hand, WARS overexpression sensitized the therapeutic response to docetaxel. Additionally, downregulation of WARS caused a decrease in the number of apoptotic cell populations by docetaxel. Poly (ADP-ribose) polymerase cleavage and caspase 3/7 activity were increased in docetaxel-treated tumor cells with WARS overexpression.ConclusionOur results suggest that WARS might be a potential predictor for chemotherapy response in patients with HR-positive breast cancer as well as a novel molecular target to improve chemosensitivity.     

mRNA expression level of estrogen-inducible gene, alpha 1-antichymotrypsin, is a predictor of early tumor recurrence in patients with invasive breast cancers

We previously identified 18 genes that correlated with ER positivity by adapter-tagged competitive-PCR analysis of 2412 genes in human breast cancer tissues. The aim of the present study was to determine the prognostic significance of these genes. mRNA expression levels of 12 of the above 18 genes were quantified in breast cancer tissues by real-time PCR assay, and their association with patients' prognosis (n = 110) was studied according to hormone receptor (HR) status. In addition, the genes found to influence prognosis were further investigated to examine whether their mRNA expression could be induced by estrogen in MCF-7 cells in vitro. Of the 12 genes, mRNA expression levels of two [alpha 1-antichymotrypsin (ACT) and stanniocalcin 2 (STC2)] were significantly (P = 0.002 and P = 0.007, respectively) associated with good prognosis in HR-positive (ER and/or PR positive) breast cancer patients treated with adjuvant hormone therapy. Multivariate analysis showed that ACT mRNA level, but not STC2 mRNA level, in HR-positive patients, was a significant prognostic factor (P = 0.042), which was independent of tumor size and lymph node metastases. On the other hand, mRNA expressions of ACT and STC2 were not significantly associated with prognosis in HR-negative patients. Estradiol treatment resulted in a significant increase in the mRNA levels of both ACT and STC2 in MCF-7 cells. The mRNA level of ACT, which is an estrogen-inducible gene, is a significant predictor of good prognosis in HR-positive, but not HR-negative, patients with breast cancers. Since HR-positive patients were treated with adjuvant hormone therapy, we suggest that ACT mRNA level could potentially be used as a predictor of response to hormone therapy, rather than a prognostic factor (predictor of metastatic potential).     

The prognostic and predictive role of 21-gene recurrence scores in hormone receptor-positive early-stage breast cancer

Over the past two decades, gene expression profiling of breast cancer has emerged as an important tool in early-stage breast cancer management. The approach provides important information on underlying biological mechanisms, breast cancer classification, future risk potential of developing recurrent metastatic disease, and provides beneficial clues for adjuvant chemotherapy in hormone receptor (HR) positive breast cancer. Of the commercially available genomic tests for breast cancer, the prognostic and predictive value of 21-gene recurrence score tests have been validated using both retrospective data and prospective clinical trials. In this paper, we reviewed the current evidence on 21-gene expression profiles for HR-positive HER2-negative early-stage breast cancer management. We show that current evidence supports endocrine therapy alone as an appropriate adjuvant systemic therapy for approximately 70% of women with HR-positive, HER2-negative, node-negative breast cancer. Evolving evidence also suggests that 21-gene recurrence scores have predictive values for node-positive breast cancer and that chemotherapy can be avoided in more than half of women with nodes 1 to 3 positive HR-positive breast cancer. Furthermore, retrospective data also supports the predictive role of 21-gene recurrence scores for adjuvant radiation therapy. A prospective trial in this area is ongoing.     

Immune Checkpoint Blockade in Hormone Receptor-Positive Breast Cancer: Resistance Mechanisms and Future Perspectives

Anti-programmed cell death protein 1 immunotherapy has been incorporated in the treatment algorithm of triple-negative breast cancer (TNBC). However, clinical trial results for patients with hormone receptor (HR)-positive disease appear less compelling. HR-positive tumors exhibit lower levels of programmed death-ligand 1 expression in comparison with their triple-negative counterparts. Moreover, signaling through estrogen receptor alters the immune microenvironment, rendering such tumors immunologically “cold.” To explain differential responses to immune checkpoint blockade, this review interrogates differences between HR-positive and TNBC. Starting from distinct genomic features, we further present disparities concerning the tumor microenvironment and finally, we summarize early-phase clinical trial results on promising novel immunotherapy combinations.     

LMAN2在HR阳性乳腺癌组织中的表达与患者预后的关系及其对MCF-7细胞增殖和迁移的影响

目的：探究甘露糖结合凝集素2(LMAN2)在激素受体（HR）阳性乳腺癌组织中的表达水平与乳腺癌患者预后的关系及其对MCF-7细胞增殖和迁移的影响。方法：通过TCGA、Bc-GenExMiner、GEPIA和Kaplan-Meier Plotter数据库分析LMAN2在乳腺癌组织和正常乳腺组织中的差异性表达及其与患者预后的关系。采用小RNA干扰技术将si-LMAN2#1、si-LMAN2#2及si-NC转染至MCF-7细胞,将过表达LMAN载体（pc-LMAN）及空载体pcDNA3.1阴性对照（pc-NC）转染至MCF-7细胞,实验分为si-LMAN2#1、si-LMAN2#2、si-NC、pc-LMAN2和pc-NC组。通过qPCR和WB实验检测各组细胞中LMAN2 mRNA和蛋白的表达水平,CCK-8、克隆形成、Transwell迁移、WB等实验检测敲低和过表达LMAN 2对MCF-7细胞增殖、克隆形成、迁移及AKT信号通路相关蛋白表达的影响。结果：LMAN2在乳腺癌组织中的表达水平显著高于正常乳腺组织（P<0.001）。HR阳性乳腺癌组织中LMAN2表达水平显著高于HR阴性乳...     

Clinical significance of CYLD downregulation in breast cancer

Cylindromatosis (CYLD) is a tumor suppressor gene that is mutated in familial cylindromatosis, a rare autosomal dominant disorder associated with numerous benign skin adnexal tumors. CYLD is now known to regulate various signaling pathways, including transforming growth factor-β signaling, Wnt/β-catenin signaling, and NF-κB signaling by deubiquitinating upstream regulatory factors. Downregulation of CYLD has been reported in several malignancies; however, the clinical significance of CYLD expression in many malignancies, including breast cancer, remains to be elucidated. This study investigated the clinical significance of CYLD in breast cancer and its roles in tumor progression. We evaluated CYLD expression in matched normal breast tissue samples and tumor breast tissue samples from 26 patients with breast cancer and in a series of breast cancer cell lines. In addition, by means of immunohistochemistry, we investigated CYLD protein expression and its clinical significance in 244 breast cancer cases. We also analyzed the effects of CYLD repression or overexpression on breast cancer cell viability, cell migration, and NF-κB activity with or without receptor activator of NF-κB ligand (RANKL) stimulation. Breast cancer tissues demonstrated significantly reduced CYLD mRNA expression compared with normal breast tissues. Downregulation of CYLD promoted cell survival and migratory activities through NF-κB activation, whereas CYLD overexpression inhibited those activities in MDA-MB-231 cells. As an important finding, CYLD overexpression also inhibited RANKL-induced NF-κB activation. Our immunohistochemical analysis revealed that reduced CYLD protein expression was significantly correlated with estrogen receptor negativity, high Ki-67 index, high nuclear grade, decreased disease-free survival, and reduced breast cancer-specific survival in primary breast cancer. Moreover, reduced CYLD expression was an independent factor for poor prognosis in breast cancer. CYLD downregulation may promote breast cancer metastasis via NF-κB activation, including RANKL signaling.     

Clinicopathological features and treatment strategy for triple-negative breast cancer

Breast cancers are divided into at least 4 subtypes on the basis of gene expression profiles and expression of receptors (hormone receptors (HR) and HER2) as measured by immunohistochemistry. These subtypes have different prognoses and responses to treatments such as endocrine manipulation, anti-HER2 therapy, and chemotherapy. Triple-negative breast cancer (TNBC) is immunohistochemically defined as lacking estrogen and progesterone receptors and not overexpressing HER2. TNBC accounts for approximately 15% of breast cancer patients, and is more chemosensitive but has a worse prognosis than the HR-positive/HER2-negative phenotype. TNBC is a heterogeneous disease that does not offer specific targets in the same way as HR-positive and HER2-positive breast cancers, and is similar to basal-like breast cancer and BRCA1-related breast cancer. At present, the lack of highly effective therapeutic targets for TNBC leaves standard chemotherapy, for example the combination of anthracycline and taxane, as the only medical treatment, but this is insufficiently efficacious. Novel approaches for TNBC, for example DNA damaging agents, PARP-1 inhibitors, receptor tyrosin kinase inhibitors (TKIs), and antiangiogenesis agents, have been examined in clinical settings. Concerning therapeutic strategies for TNBC, it is most important to develop novel effective approaches for TNBC treatment and high-throughput predictive tools for standard chemotherapy and novel agents.     

不同分子分型1～2枚前哨淋巴结阳性乳腺癌免行腋窝淋巴结清扫的多因素分析

目的探讨不同分子分型1～2枚前哨淋巴结（sentinel lymph nodes,SLNs）阳性乳腺癌免行腋窝淋巴结清扫（axillary lymph node dissection,ALND）的临床病理因素,并为临床精准化提供依据。方法回顾性分析2009年6月至2018年6月274例就诊于内蒙古医科大学附属医院和内蒙古医科大学附属人民医院经病理证实的乳腺癌患者的临床病理资料,采用单因素及Logistic多因素分析筛选1～2枚SLN阳性但非前哨淋巴结（nonsentinel lymph node,NSLN）转移率较低的患者,同时明确其与不同分子分型的关系。结果274例1～2枚SLN阳性乳腺癌患者中,NSLN转移率为36.9%（101/274）。HER-2阳性（HR阳性）患者NSLN转移率最高, 占55.3%（21/38）;三阴性乳腺癌（triple negative breast cancer,TNBC）患者中NSLN转移率最低,占18.5%（5/27）。Luminal B型（HER-2阴性）乳腺癌患者的NSLN转移率明显高于Luminal A型（P=0.010）和TNBC患者（P=0.011）;HER-2阳性（HR阳性）乳腺癌患者的NSLN转移率明显高于Luminal A型（P=0.002）和TNBC患者（P=0.003）。 Logistic多因素分析显示,SLN转移数目（OR=4.022, 95%CI为2.348～6.889,P<0.001）,SLN检测（OR=3.846, 95%CI为1.541～9.600,P=0.004）,组织学分级（P<0.001）和分子分型（P=0.004）是1～2枚SLN阳性乳腺癌NSLN转移的独立影响因素。结论Luminal B型（HER-2阴性）和HER-2阳性（HR阳性）患者的NSLN阳性率较高,SLN转移数目、SLN检测、组织学分级和分子分型是NSLN转移的独立影响因素。      

Endocrine Therapy for Metastatic Disease: Reversing Resistance

Growth factor receptor signaling plays a key role in endocrine resistance to therapy for metastatic breast cancer. These molecular pathways provide a unique target for new therapeutic approaches to reverse resistance. In this review, we provide a background discussion on the mechanisms of resistance, and then proceed to describe recent clinical trials involving the use of growth factor receptor inhibitors to improve patient outcome in metastatic hormone receptor (HR)-positive breast cancer. We demonstrate incremental improvements in outcome for patients with HR-positive metastatic breast cancer with combination therapy involving growth factor inhibitors and endocrine therapies. It remains unclear which patients with HR-positive metastatic breast cancer benefit from these combined approaches, and further research will focus on this issue. Understanding the mechanisms of endocrine resistance will undoubtedly lead to the development of new agents that can improve outcome for patients with this disease.     

激素受体阳性早期乳腺癌治疗现状与挑战

在早期发现、有效治疗的情况下,早期乳腺癌是可治愈的,长期无病生存应是早期患者所追求的治疗目标。既往认为乳腺癌各亚型中激素受体（hormone receptor,HR）阳性早期乳腺癌预后最好,然而随着人类表皮生长因子受体2（human epidermal growth factor receptor 2,HER2）阳性乳腺癌抗HER2靶向治疗和三阴性乳腺癌强化治疗的发展,HR阳性早期乳腺癌预后优势已不再明显。当前,术后应用他莫昔芬或芳香化酶抑制单药进行内分泌治疗是HR阳性早期乳腺癌核心辅助治疗方式,但部分患者复发风险高、长期生存情况并不乐观。为改善患者预后、提高生活质量,目前临床主要探索方向包括以下三方面：① 强化治疗。强化方式包括延长内分泌治疗、联合卵巢功能抑制等,近期研究还探索了细胞周期蛋白依赖性激酶4/6抑制剂用于HR阳性早期乳腺癌患者强化治疗的效果和安全性。同时,如何有效地辨别适合于强化治疗的高危患者亦是研究热点,乳腺癌指数、STEPP分析等已获得权威指南推荐用于辅助强化治疗决策。② 化疗降阶/免化疗：精准化疗是目前国际主流趋势,多个国际指南推荐使用多基因检测工具如MammaPrint ^® 、Oncotype DX ^® 、EndoPredict ^® 等分析结果辅助决策化疗降阶,以避免过度治疗。这些检测工具在我国患者中的临床研究和应用也日益增加,有望帮助提升我国患者获益。③ 术前内分泌治疗：尽管术前内分泌治疗可否给HR阳性早期乳腺癌患者带来直接获益尚待确认,但治疗过程中的生化指标变化与患者预后密切相关,或可在后续治疗决策（如是否可免除化疗、是否适用细胞周期蛋白依赖性激酶4/6抑制剂等）中发挥重要的指导作用,值得临床积极探索。本文将就上述HR阳性早期乳腺癌治疗的现状和研究进展进行综述和探讨,以期为临床医生提供参考。     

HER3 status by immunohistochemistry is correlated with poor prognosis in hormone receptor-negative breast cancer patients

Breast cancer is a highly heterogeneous malignancy. The triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2 (HER2) breast cancer subtypes are highly aggressive and are associated with a poor prognosis. The therapeutic targets for TNBC remain undefined, and many patients with the HER2 subtype acquire resistance to therapy after prolonged treatment. The objective of this study was to evaluate the prognostic significance of HER3 expression in invasive breast carcinoma. We established matched tissue microarray (TMA) blocks and clinical data from 950 cases of invasive breast carcinoma with long-term clinical follow-up data (median 109.7 months). Using the TMAs, we characterized the expression of ER, PR, HER2, EGFR, and HER3 by immunohistochemistry. Each case was classified as one of four IHC-based subtypes based on the expression of hormonal receptor (HR) and HER2. The clinicopathological characteristics and survival of 950 patients were analyzed by subtype. In the TNBC subtype, the HER3(+) group showed poorer disease-free survival (DFS, P = 0.010) and overall survival (OS, P = 0.015) than the HER3(?) group. In the HER2 subtype, the HER3(+) group also showed poorer DFS (P = 0.022) and OS (P = 0.077) than the HER3(?) group. However, there was no difference in patients with HR-positive breast cancer. HER3 expression was associated with poor DFS in both the TNBC and HER2 subtypes and poor OS in the TNBC subtype. HER3 overexpression is an important prognostic marker in hormone receptor-negative breast cancer, and further study is needed to clarify the role of HER-3 targeted treatment.     

2022年ASCO转移性乳腺癌的治疗进展

美国临床肿瘤学会（ASCO）2022年会的乳腺癌研究首次证实HER-2靶向治疗可改善HER-2低表达患者的生存预后,HR阳性/HER-2阴性转移性乳腺癌患者使用戈沙妥珠单抗后延长无进展生存期,驱动基因HER-3成为乳腺癌治疗的新靶点,哌柏西利联合来曲唑一线治疗的总生存结果为阴性,HR阳性/HER-2阴性转移性乳腺癌标准治疗进展后更换内分泌药物并持续CDK4/6抑制剂治疗仍可延长患者无进展生存期。本文将就此次大会中有关转移性乳腺癌治疗的重要进展进行综述。     

Adding hormonal therapy to chemotherapy and trastuzumab improves prognosis in patients with hormone receptor-positive and human epidermal growth factor receptor 2-positive primary breast cancer

Adjuvant hormonal therapy for hormone receptor (HR)-positive primary breast cancer patients and a human epidermal growth factor receptor 2 (HER2)-targeted agent for HER2-positive primary breast cancer patients are standard treatment. However, it is not well known whether adding hormonal therapy to the combination of preoperative or postoperative chemotherapy and HER2-targeted agent contributes any additional clinical benefit in patients with HR-positive/HER2-positive primary breast cancer regardless of cross-talk between HR and HER2. We retrospectively reviewed records from 897 patients with HR-positive/HER2-positive primary breast cancer with clinical stage I–III disease who underwent surgery between 1988 and 2009. We determined the overall survival (OS) and disease-free survival (DFS) rates according to whether they received hormonal therapy or not and according to the type of hormonal therapy, tamoxifen and aromatase inhibitor, they received. The median followup time was 52.8 months (range 1–294.6 months). Patients who received hormonal therapy with chemotherapy and trastuzumab (n = 128) had significantly higher OS and DFS rates than did those who received only chemotherapy and trastuzumab (n = 46) in log-rank analysis (OS 96.1 vs. 87.0 %, p = 0.023, DFS 86.7 vs. 78.3 %, p = 0.029). There was no statistical difference in OS or DFS between those given an aromatase inhibitor and those given tamoxifen. In multivariate analysis, receiving hormonal therapy in addition to the combination of chemotherapy and trastuzumab was the sole independent prognostic factor for DFS (hazard ratio 0.446; 95 % CI 0.200–0.992; p = 0.048), and there was a similar trend in OS. Our study supported that hormonal therapy, whether in the form of an aromatase inhibitor or tamoxifen, confers a survival benefit when added to chemotherapy and trastuzumab in patients with HR-positive/HER2-positive primary breast cancer. Adjuvant treatment without hormonal therapy is inferior for this patient population.     

BTG1 expression correlates with the pathogenesis and progression of breast carcinomas

This study aimed to analyze the expression, clinical significance of B cell translocation gene 1 (BTG1) in breast carcinoma and the biological effect in its cell line by BTG1 overexpression. Immunohistochemistry and western blot were used to analyze BTG1 protein expression in 72 cases of breast cancer and 36 cases of normal tissues to study the relationship between BTG1 expression and clinical factors. Recombinant lentiviral vector was constructed to over-express EMP-1 and then infect breast cancer MCF-7 cell line. Quantitative real-time RT-PCR (qRT-PCR) and western blot were used to detect the mRNA level and protein of BTG1. MTT assay, cell apoptosis, cell cycles, migration and invasion assays were also conducted as to the influence of the upregulated expression of BTG1 that might be found on MCF-7 cells biological effect. The level of BTG1 protein expression was found to be significantly lower in breast cancer tissue than normal tissues (P?<?0.05). Decreased expression of BTG1 was significantly correlated with tumor invasion, lymph node metastasis, clinic stage and histological grade of patients with breast cancer (P?<?0.05). Meanwhile, loss of BTG1 expression correlated significantly with poor overall survival time by Kaplan–Meier analysis (P?<?0.05). The result of biological function shown that MCF-7 cell transfected BTG1 had a lower survival fraction, higher percentage of the G0/G1 phases, higher cell apoptosis, significant decrease in migration and invasion, and lower CyclinD1, Bcl-2, and MMP-9 protein expression compared with MCF-7 cell untransfected BTG1 (P?<?0.05). BTG1 expression decreased in breast cancer and correlated significantly lymph node metastasis, clinic stage, histological grade, poor overall survival, proliferation, and metastasis in breast cancer cell by regulating CyclinD1, Bcl-2, and MMP-9 protein expression, suggesting that BTG1 may play important roles as a negative regulator to breast cancer cell.     

Study of time-course changes in annual recurrence rates for breast cancer: data analysis of 2,209 patients for 10 years post-surgery

Annual recurrence rates (ARR) are used to assess changes in the risk of breast cancer recurrence following surgery. In this retrospective study, ARR were calculated from the clinical records of 2,209 breast cancer patients who had undergone surgery. The time-course changes of ARR associated with prognostic/predictive factors were calculated. Overall, ARR decreased for 5 years following surgery and then remained almost constant. In hormone receptor (HR)-negative patients, ARR peaked after 2 years and peaked again at 6–7 years. In HR-positive patients, ARR peaked at 2 years. ARR increased in relation to the number of lymph-node metastases for 5 years, and peaked after 2 years in the absence and presence of venous invasion. The log-rank test demonstrated significant differences in recurrence between HR-negative and HR-positive cancer up to 5 years post-surgery. The presence of venous invasion had a significant effect on recurrence in the first 5 years, and the presence of lymph-node metastasis had a significant effect on recurrence up to and after 5 years. In conclusion, prognostic/predictive factors affected breast cancer recurrence in the first 5 years but had a lesser effect on recurrence more than 5 years post-surgery.     

乙醛脱氢酶1蛋白在乳腺癌中的表达及临床意义

目的:探讨肿瘤干细胞标志物乙醛脱氢酶1(aldehyde dehydrogenase 1,ALDH1)在乳腺癌中的表达及其临床意义.方法:采用免疫组织化学染色法检测92例乳腺癌患者肿瘤组织中ALDH1蛋白的表达,并结合临床病理特征进行相关性分析和无病生存期分析.结果:ALDH1蛋白在乳腺癌组织中的阳性表达与孕激素受体(progesterone receptor, PR)和cerb-B2有关(P<0.05),与患者年龄、肿瘤大小、临床分期以及是否有淋巴结转移无关(P>0.05).ALDH1阳性患者2年无病生存率显著低于ALDH1阴性患者(P<0.05),接受CEF方案化疗和内分泌治疗的ALDH1阳性患者2年无病生存率显著低于ALDH1阴性患者(P<0.05).结论:ALDH1蛋白表达阳性的乳腺癌患者其无病生存率降低与耐药有关,ALDH1可作为乳腺癌预后判断的指标.     

Epigenetic inactivation implies independent functions for insulin-like growth factor binding protein (IGFBP)-related protein 1 and the related IGFBPL1 in inhibiting breast cancer phenotypes.

PURPOSE: To analyze epigenetic regulation of two related genes, insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) and IGFBPL1, and its significance as a determinant of clinical phenotypes in human breast cancer. EXPERIMENTAL DESIGN: We have investigated the expression and epigenetic regulation of IGFBP-rP1 and IGFBPL1 in human breast cancer cell lines and primary and metastatic carcinomas. RESULTS: Expression of IGFBP-rP1 and IGFBPL1 is down-regulated in breast cancer cell lines. Aberrant methylation in the CpG islands of each gene correlates well with loss of expression at the mRNA level. Analysis of methylation in DNA isolated from human primary breast tumors showed that methylation in either gene was associated with a worse overall survival (OS; P=0.008) and disease-free survival (DFS) following surgery (P=0.04) and worse DFS following adjuvant chemotherapy (P=0.01). Methylation of IGFBP-rP1 alone was associated with a trend toward decreased OS (P=0.10) and decreased DFS (P=0.25). Methylation in IGFBPL1 was clearly associated with worse OS (P=0.001) and DFS (P<0.0001). Methylation in either IGFBP-rP1 or IGFBPL1 was significantly associated with nodal disease (P<0.001). CONCLUSIONS: Expression of IGFBP-rP1 and IGFBPL1 is regulated by aberrant hypermethylation in breast cancer, implying that inactivation of these genes is involved in the pathogenesis of this malignancy. Analysis of methylation of these genes may have utility in prediction of clinical phenotypes, such as nodal disease and response to chemotherapy.     

Cancer cell-associated MT1-MMP promotes blood vessel invasion and distant metastasis in triple-negative mammary tumors

Functional roles for the cancer cell-associated membrane type I matrix metalloproteinase (MT1-MMP) during early steps of the metastatic cascade in primary tumors remain unresolved. In an effort to determine its significance, we determined the in vivo effects of RNAi-mediated downregulation in mammary cancer cells on the migration, blood and lymphatic vessel invasion (LVI), and lymph node and lung metastasis. We also correlated the expression of cancer cell MT1-MMP with blood vessel invasion (BVI) in 102 breast cancer biopsies. MT1-MMP downregulation in cancer cells decreased lung metastasis without affecting primary tumor growth. The inhibition of lung metastasis correlated with reduced cancer cell migration and BVI. Furthermore, cancer cell-expressed MT1-MMP upregulated the expression of MT1-MMP in vascular endothelial cells, but did not affect MT1-MMP expression in lymphatic endothelial cells, LVI, or lymph node metastasis. Of clinical importance, we observed that elevated MT1-MMP expression correlated with BVI in biopsies from triple-negative breast cancers (TNBC), which have a poor prognosis and high incidence of distant metastasis, relative to other breast cancer subtypes. Together, our findings established that MT1-MMP activity in breast tumors is essential for BVI, but not LVI, and that MT1-MMP should be further explored as a predictor and therapeutic target of hematogenous metastasis in TNBC patients.