The relation of breast cancer staging to screening protocol compliance: a computer simulation study

A computer model based on relational database techniques was used to analyze the relationship between staging and population compliance to a breast cancer screening protocol. Stage distribution data permitted estimates of compliance to the protocol. This relationship followed the equation y=5.83e-2.44x where y was compliance and x was disease stage. Application of this equation to SEER and NCDB data estimated that the levels of compliance never exceeded 16 percent. Results indicated increasing clinical Stage IV disease as population compliance decreased. As the clinical staging increased there was increased sub-clinical Stage IV disease. With regular screening, simulation suggested that mortality would decrease.     

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。     

Expression of XB130 in human ductal breast cancer

Objectives: XB130 is involved in gene regulation, cell proliferation, cell survival, cell migration, and tumorigenesis. In the present study, we first evaluated the expression of the XB130 and its prognostic significance in breast cancer. Then we evaluated whether XB130 could be a target for therapy in breast cancer. Materials and methods: Immunohistochemistry was used to assess the level of XB130 protein in surgically resected, formalin-fixed, paraffin-embedded breast cancer specimens. Associations between XB130 and the postoperative prognosis of patients with breast cancer were evaluated. We evaluated the effect of XB130 inhibited by RNA interference on proliferation, invasion and apoptosis in vitro in a metastatic subclone of MCF-7 breast cancer cell line (LM-MCF-7). The effect of XB130 silencing alone or in combination with gemcitabine on LM-MCF-7 cells apoptosis was also investigated. Results: XB130 protein was present in the cytoplasm of malignant cells, and not in the normal breast tissues. There was correlation between the presence of XB130 in tumour cells and lymph node status, tumor classification and clinical stage. XB130 expression level was significantly associated with recurrence-free and overall survival. Furthermore, multivariate Cox regression analyses revealed that positive XB130 was an independent risk factor for overall survival and recurrence free survival. XB130 silencing alone inhibits tumor growth and induces apoptosis in the LM-MCF-7 cells. Depletion of the XB130 in combination with gemcitabine resulted in marked apoptotic and necrotic cell death in LM-MCF-7 cells. Conclusions: XB130 could be useful as a prognostic marker of recurrence-free and overall survival in invasive breast cancer, as well as for the response to chemotherapy.     

Pathobiology of breast cancer: Hypothesis of biological predetermination and long-term survival

Summary The pathobiology of breast cancer is complex: clinically early breast cancer may be tumorbiologically late progressing rapidly toward death. Accordingly, it has been suggested that two different breast cancer populations (slow tumor growth and long survival — fast tumor growth and short survival) exist, which cannot be identified by pathohistological criteria. However, these populations are most likely either patients with localized disease and occult metastases (long survival) or with diagnosable regional and occult or overt systemic spread (short survival). Since even small tumors (0.1 to 0.3 cm in diameter) can spread systemically, in most patients breast cancer upon clinical diagnosis may be considered an inevitably lethal disease. Present treatment modalities can only improve the quality of life and delay death, even though the overall long-term survival rates of breast cancer are better or at least equal to those of other cancers. However, with other cancers (Table 2) it is decided within the first 5 years which patients are cured because the survival rates for 5, 10, 15, and 20 years are similar. In contrast, survival rates of patients with breast cancer steadily decline and there is no point in time when patients can feel really safe; this is indicative of a peculiar tumor pathobiology of this disease, the nature of which remains to be investigated. Progress in the fight against breast cancer is only possible by application of sensitive physical, reliable immunological, and specific biochemical methods for early diagnosis and development of efficient therapeutic modalities for inhibition of growth or complete eradication of metastasized cancer cells.     

Correlation between tumor suppressor inhibitor of growth family member 4 expression and microvessel density in breast cancer

Suppression of cell spreading and migration by inhibitor of growth 4 suggests that its loss may induce metastasis. Inhibitor of growth 4 expression level in 60 breast cancer tissues, 30 normal adjacent tissues, and tissues from patients with benign hyperplasia was determined by real-time polymerase chain reaction, Western blot, and immunohistochemistry. The correlation between inhibitor of growth 4 expression and clinical stage, histologic grade, and microvessel density in breast cancer was analyzed. Inhibitor of growth 4 messenger RNA and protein expression in breast cancer was significantly lower than that observed in adjacent normal and hyperplastic breast tissues (P < .05). Inhibitor of growth 4 expression decreased with increasing clinical stage and histologic grade. Moreover, the presence of lymph node metastasis was correlated with decreased inhibitor of growth 4 messenger RNA expression (P < .01), and a negative correlation was noted between inhibitor of growth 4 protein expression and microvessel density in breast cancer. Inhibitor of growth 4 may represent an important biomarker for assessing the severity of breast cancer. Further studies are required to fully evaluate the diagnostic and possible prognostic value of determining inhibitor of growth 4 levels in breast cancer.     

外侧组织瓣转移用于保留乳房的乳癌根治术

目的 探讨乳腺癌根治手术的同时进行乳房成形的术式及其临床意义。方法 自1997年至2002年对20例早期原发乳腺癌进行乳房成形的根治术。结果 20例手术均获成功,切口均甲级愈合,无乳头坏死。其中10例患者术后2年以上随访,均无肿瘤局部复发及转移。与不保留乳房的根治手术相比肿瘤的复发和生存差异无显著性。乳房成形根治术按lino Y美观标准评价,优15例,良5例。结论 随着医学模式的改进,对乳腺癌手术治疗原则已经转为由大到小的趋势,在充分切除原发癌的前提下,尽量采用破坏性较小的术式,重视保留乳房的美学理念。应用外侧软组织瓣(lateral tissue flap,LTF)乳房成形,显示出良好临床效果和使用价值。     

Expression of cyclin kinase subunit 2 in human breast cancer and its prognostic significance

Cyclin kinase subunit 2 (CKS2) protein is a small cyclin-dependent kinase-interacting protein, which is essential for the first metaphase/anaphase transition of mammalian meiosis. CKS2 is up-regulated in various malignancies, suggesting that CKS2 maybe an oncogene. However, data on its expression pattern and clinical relevance in breast cancer are unknown. The aim of this study is to investigate CKS2 expression and its prognostic significance in breast cancer. The CKS2 expression was examined at mRNA and protein levels by real-time quantitative polymerase chain reaction (RT-PCR) and Western blotting analysis in paired breast cancer tissues and the adjacent normal tissues. The expression of CKS2 protein in 126 specimens of breast cancer was determined by immunohistochemistry assay. The relations between CKS2 expression and clinicopathological features were analyzed. The result show the expression of CKS2 mRNA and protein was higher in breast cancer than the adjacent normal tissues. Compared with adjacent normal breast tissues, Overexpression of CKS2 was detected in 56.3% (71/126) patients. Overexpression of CKS2 was significantly associated with large tumor size (P = 0.035), poor cellular differentiation (P = 0.016), lack expression of progesterone receptor (P = 0.006), and decreased overall survival (P = 0.001). In multivariate analysis, CKS2 expression was an independent prognostic factor for overall survival (Hazard ratio [HR] = 3.404, 95% confidence interval [CI] 1.482-7.818; P = 0.004). CKS2 is up-regulated in breast cancer and associated with large tumor size, lack expression of progesterone receptor, poor tumor differentiation and survival. CKS2 may serve as a good prognostic indicator for patients with breast cancer.     

Expression of Yes-associated protein (YAP) in metastatic breast cancer

The purpose of this study was to investigate the expression of Yes-associated protein (YAP) in different metastatic sites in metastatic breast cancer and to determine the clinical implications of these patterns. Immunohistochemical staining was used to investigate the expression of YAP and phospho-YAP in tissue microarrays from 122 cases of metastatic breast cancer (bone metastasis = 29, brain metastasis = 38, liver metastasis = 12, and lung metastasis = 43). The expression levels of YAP and phospho-YAP differed according to the metastatic site in metastatic breast cancer. Specifically, nuclear expression of phospho-YAP was high in brain metastasis but low in lung metastasis (P = 0.010). The effects of YAP and phospho-YAP expression on clinical outcomes were investigated by univariate analysis. This analysis showed that nuclear YAP positivity (P = 0.008) and nuclear phospho-YAP positivity (P = 0.003) were both associated with shorter overall survival. In conclusion, the level of YAP expression varies according to the metastatic site in metastatic breast cancer. Moreover, high YAP expression was correlated with poor prognosis.     

乳腺癌中RIN1的表达及临床意义

目的 研究RIN1在乳腺癌中的表达,分析它与乳腺癌预后的关系.方法 用免疫组化SP法检测85例乳腺癌和20例乳腺良性病变组织中RIN1的表达,并对85例乳腺癌病例进行随访;用real-time PCR和Western blot 法检测RIN1在20例乳腺癌和癌旁组织中的表达.Kaplan-Meier分析生存结果.结果 85例乳腺癌标本中RIN1有不同程度表达,其中44例高表达,乳腺癌中RIN1的表达明显高于非癌组织(P＜0.05);RIN1高表达与肿瘤最大直径、组织学分级、肿瘤家族史成正相关(P＜0.05);RIN1高表达患者的平均生存时间低于RIN1低表达患者(P＜0.05);RIN1高表达影响肿瘤无病生存率(P＜0.05).20例标本中RIN1的mRNA及蛋白在乳腺癌的表达明显高于癌旁组织(P＜0.05).结论 RIN1影响乳腺癌的发生发展,其高表达RIN1可能成为判断乳腺癌预后的一个标志物.     

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.     

Obesity and high neutrophil-to-lymphocyte ratio are prognostic factors in non-metastatic breast cancer patients

Obesity has been associated with an increased risk of breast cancer recurrence and death. Some readily available biomarkers associated with systemic inflammation have been receiving attention as potential prognostic indicators in cancer, including neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). This study aimed to explore the correlation between body mass index (BMI) and invasive breast cancer and the association of NLR, PLR, and BMI with breast cancer outcomes. We undertook a retrospective study to evaluate patients treated for breast cancer over 14 years. Clinicopathological data was obtained before receiving any treatment. Of the 1664 patients included with stage I-III, 567 (34%) were obese (BMI≥30 kg/m²). Obese patients had larger tumors compared to non-obese patients. Higher BMI was associated with recurrence and worse survival only in patients with stage I disease. NLR and PLR were classified into high and low level groups. The NLR^high (NLR>4) was found to be an independent prognostic factor for recurrence and mortality, while the PLR^high (PLR>150) group had no impact on survival. A subgroup of patients with NLR^high and BMI^high had the worst disease-free survival (P=0.046), breast cancer-specific survival (P<0.001), and overall survival (P=0.006), compared to the other groups. Patients with early-stage breast cancer bearing NLR^high and BMI^high had worse outcomes, and this might be explained by the dysfunctional milieu of obesity in adipose tissue and its effects on the immune system. This study highlights the importance of lifestyle measures and the immune system interference with clinical outcomes in the early breast cancer setting.     

The combination of high cyclin E and Skp2 expression in breast cancer is associated with a poor prognosis and the basal phenotype

Gene expression studies have identified a basal phenotype of breast cancer; these are hormone receptor and HER2-negative cancers with poor prognosis. High levels of cyclin E and Skp2, and low levels of p27 have previously been individually associated with both basal-like breast cancer and a poor outcome after diagnosis. The goal of this study was to first confirm the prognostic value of these biomolecular markers using a breast cancer tissue microarray. Second, we also test the hypothesis that the combined phenotype of high cyclin E, low p27, and high Skp2 would be a strong predictor of outcome and would be closely associated with the basal phenotype of breast cancer. Our cohort consisted of 438 cases of breast cancer and the median follow-up was 15.4 years. The tissue microarray was constructed from archival tumor blocks and we used commercially available antibodies for biomarker immunostaining. Cyclin E was positive in 46% of cases, p27 was negative in 62%, and Skp2 was positive in 35%. We found cyclin E and Skp2 to be prognostic for breast cancer-specific survival in univariate analyses, but p27 was not prognostic. The strongest predictor of outcome was the combination of cyclin E positive and Skp2 positive (difference in survival of 19% at 10 years, P = .0009). This combination was present in 78 (27%) of 288 cases for which data on both biomarkers were available. This combination was also highly associated with young age at diagnosis, grade 3 tumors, ER-negative status, HER2-negative status, and the basal biomarkers epidermal growth factor receptor and cytokeratin 5/6. However, in a multivariate model including standard clinicopathologic variables, this combination was not found to have independent prognostic significance. In conclusion, the combination of high cyclin E and Skp2 expression predicts for poor prognosis in breast cancer in univariate analysis only, it is associated with high risk features, and it is associated with the basal phenotype.     

Notch1受体在乳腺癌组织中的表达及其与临床病理特征的关系

目的 探讨Notch1受体与乳腺癌患者的临床病理特征及预后的关系.方法 应用免疫组化技术检测106例乳腺癌组织中Notch1受体、ER、PR、CerbB-2受体表达情况,分析其与临床病理特征及预后的相关性.结果 乳腺癌组织中Notch1受体表达明显高于癌旁正常组织(P＜0.05);Notch1受体表达与CerbB-2具有相关性(P＜0.05),与ER、PR无显著相关性(P＞0.05);Notch1受体高表达组5年生存率低于低表达组(P＜0.05).结论 乳腺癌组织中Notch1受体表达明显高于癌旁正常组织;Notch1受体表达与CerbB-2具有相关性,推测Notch1受体可能与CerbB-2存在交互作用;Notch1受体高表达与预后不良有关.     

Numerical modelling of biopotential field for detection of breast tumour

Breast cancer is a disease characterised by the uncontrolled growth of abnormal cells. These cancer cells can travel through the body by way of blood or lymph nodes. Previous studies have indicated that, changes in the electrical properties of abnormal breast are more significant compared to the breast normal tissues. In the present study, a simple 2D models of breast (close to realistic), with and without artificially inserted malignant cancer were simulated, based upon electrical activity within the breast. We developed an inhomogeneous female breast model, closer to the actual, by considering a breast as a hemisphere with various layers of unequal thickness in supine condition. In order to determine the potential distribution developed due to a dipole source, isotropic homogeneous conductivity was assigned to each of these compartments and the volume conductor problem was solved using finite element method. Significant changes in the potential distribution were recoded in the malignant and normal breast regions. The surface potential decreases about 0.5%, for the small malignant region of surface area 13 mm(2) (spherical diameter=2mm). And it (surface potential) decreases about 16.4% for large malignant surface area of 615 mm(2) (spherical diameter=14 mm). Hence, the results show that, the sizes of tumours result in the reduction of surface potential and follows a fourth order polynomial equation. Thus, biofield analysis yields promising results in the detection of the breast cancer of various sizes.     

Breast cancer cell surface annexin II induces cell migration and neoangiogenesis via tPA dependent plasmin generation

Annexin II, an abundant phospholipids binding cell surface protein, binds tPA and functions as a regulator of fibrinolysis. Annexin II also mediates angiogenesis and enhances tumor growth and metastasis. However, the mechanism supporting this role is not known. Using human breast cancer model we show that invasive human breast cancer cells (MDA-MB231) synthesize annexin II and tissue plasminogen activator (tPA). In vitro both annexin II and tPA interacts which in turn convert zymogen plasminogen to reactive enzyme plasmin. Cell surface produced plasmin inhibited the migration of MDA-MB231 cells. Silencing of annexin II gene in MDA-MB231 cells abolished tPA binding therefore inhibited tPA dependent plasmin generation. These annexin II suppressed MDA-MB231 cells showed reduced motility. Immunohistochemical analysis of prediagnosed clinical specimens showed abundant secretion of tPA and expression of annexin II on the surface of invasive human breast cancer cells which correlates with neovascularization of the tumor. Taken together, these data indicate that annexin II may regulate localized plasmin generation in breast cancer. This may be an early event switching breast cancer from the prevascular phase to the vascular phase and thus contributing to aggressive cancer with the possibility of metastasis. The data provide a mechanism explaining the role of annexin II in breast cancer progression and suggest that annexin II may be an attractive target for therapeutic strategies aimed to inhibit angiogenesis and breast cancer.     

一种新型转移诱导蛋白AGR2在乳腺癌中的表达及其临床和预后意义

目的 研究转移诱导蛋白AGR2在人乳腺癌中表达和意义及其与患者预后的关系.方法 采用组织芯片,应用免疫组织化学方法检测160例乳腺癌和20例乳腺良性病变组织AGR2表达,以及乳腺癌ERα、PR和HER2表达状况,并用Kaplan-Meier曲线法和Log-rank检验对有随访资料的127例进行与AGR2的相关性分析.结果 乳腺癌AGR2表达量较乳腺良性病变显著性增高(68.3%和25.0%,P＜0.01);AGR2表达与乳腺癌组织学分级呈负相关(P＜0.05),与乳腺癌ERα和PR表达呈正相关(分别为P＜0.05和P＜0.01);Logistic回归模型显示AGR2和TNM分期是ERa阳性乳腺癌淋巴结转移重要的影响因子(均P＜0.01);Kaplan-Meier生存曲线显示ERα阳性乳腺癌患者中,AGR2阳性患者总生存率和无复发生存率均显著低于阴性患者(均P＜0.01),COX比例风险模型分析也证实AGR2蛋白表达是ERα阳性乳腺癌患者独立的预后影响因子(P＜0.01).结论 AGR2表达异常可能参与了乳腺癌的发生、发展过程,该机制可能部分依赖雌激素受体途径发挥其诱导肿瘤转移作用.AGR2可能是一个潜在的分子标记物,对雌激素受体阳性乳腺癌患者的预后评估有一定提示作用.