Prognostic value of nuclear hepatoma-derived growth factor (HDGF) localization in patients with breast cancer

Hepatoma-derived growth factor (HDGF) plays an important role in tumor progression. Highly expressed HDGF has been found to indicate poor prognosis in many cancers. However, no information is available regarding the prognostic value of nuclear or cytoplasmic HDGF staining level in breast cancer. In the present study, the nuclear or cytoplasmic HDGF staining level was investigated in 86 patients with primary breast cancer by immunohistochemistry; the relationship between nuclear or cytoplasmic HDGF staining level and clinicopathological parameters was examined by Two-tailed Mann-Whitney U-test or Krustal-Wallis. The prognostic value of nuclear or cytoplasmic HDGF staining level in disease-free survival and overall survival was analyzed by Kaplan-Meier methods and log-rank test. We found that the percentage of cases with strong nuclear HDGF staining level was significantly higher in the cases with high tumor grade, high stage, high proliferation index (Ki-67 index>20%), as well as in those with lymph node invasion and recurrence (p<0.05) compared to those without. No significant correlation was found between cytoplasmic HDGF expression and any clinicopathological variables. In addition, disease-free survival and overall survival were significantly lower in patients with high nuclear HDGF expression (level 2) than in those with low nuclear HDGF expression (level 0 and level 1). Further Cox multivariate analysis showed that high nuclear HDGF expression is an independent factor for indicating poor prognosis in breast cancer patients. No significant difference in disease-free survival rate and overall survival was found between different cytoplasmic HDGF staining levels. All these findings suggest that increased nuclear HDGF expression is involved in tumor progression and might be used as a new prognosticator for breast cancer.     

Overexpression of kin of IRRE-Like protein 1 (KIRREL) as a prognostic biomarker for breast cancer

ObjectivesThe purpose of this study was to investigate the expression of Kin of IRRE-Like Protein 1 (KIRREL) and its clinicopathologic significance in breast cancer.Materials and methodsThe mRNA and protein expressions of KIRREL in fresh breast cancer tissue specimens and the corresponding noncancerous tissue specimens were examined by western blot analysis (n = 24) and RT-qPCR (n = 48). KIRREL was detected by immunohistochemistry (IHC) using breast cancer tissue microarrays (TMAs) in 302 patients. The prognostic roles and clinicopathologic significances in breast cancer were statistically analyzed.ResultsCompared with para-carcinoma tissues, KIRREL mRNA and protein were overexpressed in breast cancer tissues. Immunohistochemical results showed that the high expression rate of KIRREL staining in breast cancer was 43.7% (132/302). Moreover, Expression of KIRREL was significantly correlated with Her2 status and survival outcomes of patients. Patients with both positive expression of KIRREL showed shorter overall survival (OS) and progression free survival (PFS). Additionally, Cox multivariate survival analysis revealed that KIRREL level, age, primary tumor size, tumor stage and distant metastasis were the independent parameter predicting the prognosis of breast cancer patients.ConclusionsKIRREL was overexpressed in breast cancer and the overexpression of KIRREL could serve as an independent predictor of poor prognosis in breast cancer patients.     

HPD overexpression predicts poor prognosis in breast cancer

BackgroundThe enzyme, 4-hydroxyphenylpyruvate dioxygenase (HPD), is critical to tyrosine metabolism; its deficiency can cause tyrosinemia. However, its precise contribution to tumorigenesis is unclear. Here, we investigated the correlation between HPD expression and prognosis in patients with breast cancer.Methods145 breast cancer specimens were selected to analyze HPD protein expression by immunohistochemistry and evaluate its relationship to patients’ clinicopathological features. HPD localization was confirmed in MCF-7 and MDA-MB-231 breast cancer cells, using immunofluorescence staining. The expression of HPD protein was detected in breast cancer and cancer-adjacent normal tissues using Western blot analysis. Survival rates were calculated by the Kaplan–Meier method.ResultsWe found that HPD protein was mainly located in the cytoplasm/nucleoli/perinucleus in breast cancer cells, as shown by immunofluorescence staining in MCF-7 and MDA-MB-231 cells, and immunohistochemistry in breast cancer and adjacent normal tissues (HPD protein expression—breast cancer: 46.9% [68/145], ductal carcinoma in situ [DCIS]: 22.6% [12/53], and normal tissues: only 4.8% [2/42]). Similarly, the Western blot results further confirmed the increased expression of HPD in breast cancer compared with cancer-adjacent normal tissues (P < 0.05). HPD expression level was positively correlated with histological grade and clinical stage, and inversely correlated with 10-year overall survival (OS) rates, in patients with breast cancer. Among patients with breast cancer, those with high HPD expression had worse OS rates than those with low HPD expression. Additionally, when patients were subgrouped by disease stage or grade, those with high HPD expression had worse OS rates than those with low HPD expression for each respective stage or grade.ConclusionsOur findings indicate that HPD may be a useful prognostic predictor, and a potential therapeutic target for patients with breast cancer.     

The therapy of gefitinib towards breast cancer partially through reversing breast cancer biomarker arginine

Background

Breast cancer remains the leading reason of cancer death among women worldwide, and gefitinib is the efficient drug for breast cancer.

Aims

To use targeted metabolomics method to elucidate the therapeutic mechanism of gefitinib through profiling the amino acids.

Methods

Healthy women (n=56) and women with breast cancer (n=60) were enrolled in Affiliated Yuhuangding hospital, medical college of Qingdao University from 2012–2014. API 3200 triple quadrupole mass spectrometer was used to analyze the serum samples.

Results

The concentration of amino acids was compared between healthy women and women with breast cancers. Compared with the healthy women, the concentration of arginine in breast cancer women significantly decreased (p<0.0001). To show the representative capability of arginine towards the pathogenesis of breast cancers, the receiver operating characteristic (ROC) curve was drawn, and the area under the curve (AUC) was calculated to be 0.96 ± 0.02, indicating the high predictive capability of arginine for breast cancer . The reversing ability of gefitinib towards the level of arginine was further determined, and 1 month treatment of gefitinib (500 mg/day) significantly reversed the arginine level of breast cancer patients (p<0.0001)

Conclusion

The therapy of gefitinib towards breast cancer through reversing breast cancer biomarker arginine was demonstrated.     

Loss of p27kip1 expression is associated with poor prognosis in patients with taxane-treated breast cancer

Purpose

Decreased expression of p27^kip1 and p57^kip2 is considered as a prognostic indicator in patients with breast cancer receiving adjuvant chemotherapy. Previous in vitro studies have reported that reduced expression of p27^kip1 and p57^kip2 is associated with resistance to taxane, which is one of the most effective chemotherapeutic agents. In this study, we investigated the association of low p27^kip1 and p57^kip2 expression with outcomes in patients with breast cancer.

The DietCompLyf study: A prospective cohort study of breast cancer survival and phytoestrogen consumption

DietCompLyf is a multi-centre prospective study designed to investigate associations between phytoestrogens – naturally occurring plant compounds with oestrogenic properties – and other diet and lifestyle factors with breast cancer recurrence and survival. 3159 women with grades I–III breast cancer were recruited 9–15 months post-diagnosis from 56 UK hospitals. Detailed information on clinico-pathological, diet, lifestyle and quality of life is collected annually up to 5 years. Biological samples have also been collected as a resource for subsequent evaluation. The characteristics of the patients and associations between pre-diagnosis intake of phytoestrogens (isoflavones and lignans; assessed using the EPIC-Norfolk UK 130 question food frequency questionnaire) and breast cancer (i) risk factors and (ii) prognostic factors are described for 1797 women who had complete data for all covariates and phytoestrogens of interest. Isoflavone intakes were higher in the patients who were younger at diagnosis, in the non-smokers, those who had breast-fed and those who took supplements. Lignan intakes were higher in patients with a higher age at diagnosis, in ex-smokers, those who had breast-fed, who took supplements, had a lower BMI at diagnosis, lower age at menarche and were nulliparous. No significant associations between pre-diagnosis phytoestrogen intake and factors associated with improved breast cancer prognosis were observed. The potential for further exploration of the relationship between phytoestrogens and breast cancer recurrence and survival, and for the establishment of evidence to improve dietary and lifestyle advice offered to patients following breast cancer diagnosis using DietCompLyf data is discussed.     

乳腺癌组织学分级及预后因素分析

目的探讨乳腺癌组织学分级与预后的关系。方法参照ＢｌｏｏｍＲｉｃｈａｒｄｓｏｎ和Ｅｌｓｔｏｎ的方法，对有５年以上随访资料的４７６例浸润性导管癌按腺管形成、核的多形性和核分裂相计数进行组织学分级。结果在浸润性导管癌中，Ⅰ级（７２例）、Ⅱ级（２１６例）和Ⅲ级（１８８例）的５年生存率分别为８１９％（５９例）、６３４％（１３７例）和４９５％（９３例），３级之间差异分别有显著性意义（Ｐ＜０．０１）。结论在非特殊型浸润性导管癌中，组织学分级同临床分期一样，是一个较好的预后指标     

Primary relapse site pattern in women with triple-negative breast cancer

Despite the remarkable improvements in breast cancer (BC) characterization, accurate prediction of BC clinical behavior is often still difficult to achieve. Some studies have investigated the association between the molecular subtype, namely the basal-like BC and the pattern of relapse, however only few investigated the association between relapse pattern and immunohistochemical defined triple-negative breast cancers (TNBCs). The aim of this study was to evaluate the pattern of relapse in patients with TNBC, namely the primary distant relapse site.     

乳腺癌细胞株MCF-7/ADM中肿瘤干细胞的研究

目的： 通过对阿霉素耐药乳腺癌细胞系MCF-7/ADM中乳腺癌干细胞（breast cancer stem cells,BCSCs）成分分析，观察化疗耐药处理的MCF-7乳腺癌细胞株是否可高效富集乳腺癌干细胞，为研究乳腺癌的发病机制提供思路。方法: MTT法分别测定阿霉素耐药乳腺癌细胞系MCF-7/ADM及其亲本细胞株MCF-7对阿霉素的IC50，计算其耐药倍数。通过细胞侧群（side population,SP）分析、球囊培养、流式细胞仪检测MCF-7/ADM及MCF-7中CD+44CD-24细胞比例三方面鉴定MCF-7/ADM和MCF-7中乳腺癌干细胞比例。结果: 阿霉素耐药乳腺癌细胞系MCF-7/ADM相对于MCF-7对阿霉素的耐药倍数为37.1；MCF-7/ADM中SP细胞比例为（9.60±0.66）%，MCF-7细胞的SP细胞比例为（0.39±0.11）%；两者球囊形成率分别为 （10.27±0.64）%和（1.03±0.15）%；两者的CD+44CD-24细胞比例分别为（64.87±3.87）%和（3.70±0.53）%,差异显著（P<0.05）。结论: 阿霉素耐药乳腺癌细胞系MCF-7/ADM中乳腺癌干细胞比例明显高于MCF-7细胞。化疗耐药处理的MCF-7乳腺癌细胞株可高效富集乳腺癌干细胞，这对于乳腺癌发病机制的研究具有重要意义。     

Obesity is associated with a poorer prognosis in women with hormone receptor positive breast cancer

Objective

Whether moderate to severe obesity (body mass index (BMI) ≥ 30 to <40 kg/m²) contributes to breast cancer recurrence and mortality remains uncertain.

Subjects and methods

1199 women, recruited within 12 months of their diagnosis of hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2−) invasive breast cancer completed an enrolment questionnaire and an annual follow-up questionnaire every 12 months for another 5 years. The impact of obesity on time to either local or distant recurrence or new breast cancer, or death due to breast cancer was determined by Cox regression. Women in the most extreme categories of BMI (<18.5 and ≥40) were excluded from the analysis.

Results

Of the 1155 included women, mean age, 58.4 ± 11.6 years, 53.8% had Stage 1 disease and 88.9% received oral adjuvant endocrine therapy (OAET) within 2 years of diagnosis. The likelihood of an event was significantly associated with moderate to severe obesity (HR = 1.71, 95%CI, 1.12–2.62, p = 0.014), disease beyond Stage 1 (HR = 2.87, 95% CI 1.73–4.75, p < 0.001), OAET (HR = 0.26, 95%CI 0.14–0.46, p < 0.001), mastectomy (HR = 3.28, 95%CI 1.98–5.44, p < 0.001) and radiotherapy (HR = 2.12, 95%CI 1.24–3.63, p = 0.006). For Stage 1 disease, only moderate to severe obesity (HR 3.23, 95%CI 1.48–7.03, p = 0.003) and OAET use (HR 0.41, 95%CI 0.17–0.98, p = 0.046) were significantly associated with an event.

Conclusion

Moderate to severe obesity is associated with a poorer invasive breast cancer prognosis; this is also true for women with Stage 1 disease, and is independent of age and treatment.     

The prognostic value of tumor budding in invasive breast cancer

We investigated the prognostic value of tumor budding in 160 cases of operable invasive ductal carcinoma, not otherwise specified (IDC-NOS). The number of buds was counted in H&E slides with a maximal invasive margin in a 0.950 mm² field of vision (200×). According to a cut-off score selected by ROC analysis, the cohort was dichotomized into a low (0–7 budding foci, 107 cases, 66.9%) and a high-grade budding group (8 or more budding foci, 53 cases, 33.1%). The inter-observer test showed a good reproducibility with 0.717 as the К value. High-grade budding was significantly associated with the presence of lymphovascular invasion (LVI) (P = 0.001), larger tumor size (P = 0.014), and worse clinical outcome (P < 0.001). By immunohistochemical staining, budded cells at the margin displayed epithelial mesenchymal transition (EMT)-like molecular phenotype and decreased proliferative activity. Survival analyses revealed that tumor budding (HR 4.275, P < 0.001) together with tumor size (HR 2.468, P = 0.002), node status (HR 2.362, P < 0.001), and LVI status (HR 1.910, P = 0.035) was the independent prognostic factor in IDC-NOS. In conclusion, tumor budding is a reproducible, significant, and independent histopathological prognostic factor in IDC-NOS.     

Distribution of molecular breast cancer subtypes among Tunisian women and correlation with histopathological parameters: A study of 194 patients

According to the immunohistochemical test of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (Her-2), breast cancer can be divided into 4 molecular subtypes: luminal A, luminal B, Her-2, and basal-like. The purpose of this study is to correlate these subtypes with clinicopathological features.     

紫杉醇对乳腺癌细胞紫杉醇耐药基因Txr1表达的影响

目的应用人乳腺癌细胞制备紫杉醇耐药细胞模型,探讨紫杉醇对乳腺癌细胞中紫杉醇耐药基因Txr1表达的影响。方法比较紫杉醇预处理前后不同浓度紫杉醇对乳腺癌细胞的增殖和细胞周期的改变;用RT-PCR方法检测Txr1、TSP1和MDR1的mRNA水平变化;用Western blot检测Txr1和TSP1的蛋白质水平的变化。结果紫杉醇预处理后,紫杉醇抑制乳腺癌细胞(MCF-7细胞)的生长作用明显减弱。流式细胞仪分析表明,MCF-7细胞经过紫杉醇作用后被阻滞于细胞周期的G2M期。紫杉醇作用于MCF-7细胞后,Txr1的mRNA水平上调,TSP1下调,而MDR1表达无明显改变。类似的结果在蛋白的水平被Western blot进一步证实。结论紫杉醇可能通过Txr1上调抑制TSP1的表达从而诱导肿瘤细胞的耐药性。     

A computer model for the study of breast cancer

A computer model was designed as a relational database to assess breast cancer screening in a cohort of women where the growth and development of breast cancer originates with the first malignant cell. The concepts of thresholds for growth, axillary spread, and distant sites are integrated. With tumor diagnosis, staging was performed that includes clinical and sub-clinical states. The model was parameterized to have staging characteristics similar to data published by the Surveillance, Epidemiology, and End-Results (SEER) Program. Validation was accomplished by comparing simulated staging results with non-SEER sources, and simulated survival with independent clinical survival data.     

一种新的乳腺癌预后标志物——着丝粒蛋白M

目的 着丝粒蛋白M（CENP-M）是组成型着丝粒相关网络（CCAN）蛋白家族的一名重要成员,它可以保证着丝粒、动粒的正确形成和功能行使,在细胞正常分裂中发挥重要作用。但是目前有关CENP-M与癌症的研究很少。因此,本实验旨在探讨CENP-M的表达水平与乳腺癌预后之间的关系。方法 利用Oncomine 数据库、COSMIC数据库、bc-GenExMiner、Kaplan-Meier plotter、cBioPortal、GEPIA和Timer数据库系统,分析CENP-M 的表达和乳腺癌预后情况。结果 与正常组织相比,CENP-M在乳腺癌组织（尤其在侵袭性导管乳腺癌、侵袭性筛状乳腺癌和黏液性乳腺癌）中表达上调;基因突变分析表明,CENP-M表达增加不是由基因序列或拷贝数的改变引起的;CENP-M的表达和乳腺癌不同分型以及Scarff-Bloom-Richarolsn(SBR)分级相关;CENP-M高表达的乳腺癌患者预后较差;乳腺癌中CENP-M的表达和CDC45的表达相关。结论 CENP-M可以作为乳腺癌患者的预后标志物。     

Prognostic role of syncytin expression in breast cancer

Breast cancer cells were recently found to produce syncytin, an endogenous retroviral protein implicated in cell fusion, immune regulation, and nitric oxide synthase expression. To determine whether syncytin has a prognostic role in breast cancer, we investigated a series of 165 premenopausal lymph node-negative women for syncytin expression using an immunocytochemical scoring system. Results were analyzed with the Kaplan-Meier method and with the Cox proportional hazard model. Syncytin expression was observed in 38% of the patients, and the degree of syncytin expression constituted a positive prognostic indicator for recurrence-free survival. In addition, we examined a second series of 54 consecutively operated breast cancer patients of all categories and the results supported the conclusions made from the first study. Thus, syncytin expression constitutes a positive prognostic factor in breast cancer--a phenomenon that may be related to the involvement of syncytin in mediating fusions between breast cancer cells and endothelial cells.     

Intracystic papillary carcinoma of the breast: Experience of a major Chinese cancer center

Background

Intracystic papillary carcinoma (IPC) is a rare breast neoplasm. There are few studies focusing on its clinical features and limited data about its preoperative diagnosis,treatment and outcomes. The purpose of this study is to explore specific characteristics of patients with IPC, investigate its clinicopathological features, prognosis in China and confirm its surgery management.

Carbonic anhydrase IX: A promising diagnostic and prognostic biomarker in breast carcinoma

We examined the expression of carbonic anhydrase IX (CA IX) by immunohistochemical staining using monoclonal antibody M75 (Institute of Virology, Slovak Academy of Sciences, Bratislava) in a group of 38 fibroadenomas and 55 carcinomas of the breast. In each case, the intensity of staining, percentage of labeled cells and subcellular localization of CA IX were assessed. CA IX was detected in 11/38 fibroadenomas (28.9%). Weak cytoplasmic positivity was dominant in these positive cases. Immunohistochemical analysis of 55 carcinomas showed CA IX expression in 34 cases (61.8%). Membrane staining alone was observed in 27/55 carcinomas (49.1%), while cytoplasmic positivity was found in 4/55 cases (7.3%). Combined membrane and cytoplasmic immunostaining of CA IX was detected in 3/55 carcinomas (5.4%). The intensity of immunoreactivity varied from weak to strong. Under 50% of reactive cells were found in 9/38 fibroadenomas (23.6%) and in 29/55 carcinomas (52.7%). More than 50% of reactive cells were found in 2/38 fibroadenomas (5.3%) and in 5/55 carcinomas (9.1%). Statistical analysis confirmed significant differences in the subcellular localization, intensity of immunoreactivity and percentage of labeled cells in fibroadenomas and carcinomas (p < 0.05). Our results confirmed the hypothesis that expression of CA IX may represent a valuable tumor biomarker as well as a promising diagnostic and prognostic parameter in breast cancer.