EphA2在乳腺癌中的表达及其与上皮间质转化的关系

目的　研究EphA2、上皮间质转化（EMT）在乳腺癌中的表达情况及意义,探讨EphA2与EMT在乳腺癌的侵袭与转移过程中的关系。 方法　采用免疫组织化学方法检测30例乳腺纤维瘤组织和110例乳腺癌中EphA2、E-钙黏蛋白（E-cadherin）、β-连环蛋白（β-catenin）、波形蛋白（vimentin）的表达情况,分析其与乳腺癌临床病理因素的关系及EphA2、E-cadherin蛋白、β-catenin蛋白、vimentin蛋白表达的相关性。 结果　在30例乳腺纤维瘤组织中EphA2、E-cadherin蛋白、β-catenin蛋白、vimentin蛋白阳性率分别为20%、90%、26.67%、13.33%,在110例乳腺癌中的阳性率分别为61.82%、34.54%、64.54% 、68.18%。EphA2的高表达、E-cadherin蛋白的低表达、β-catenin蛋白和vimentin蛋白的高表达与临床分期、淋巴结转移、组织学分级显著相关（P<0.05）,EphA2的高表达与E-cadherin蛋白的低表达呈负相关（P<0.05）,与β-catenin蛋白、vimentin蛋白的高表达呈正相关（P<0.05）。 结论　EphA2、E-cadherin蛋白、β-catenin蛋白、vimentin蛋白与乳腺癌的侵袭与转移有相关性;EphA2可能通过调控E-cadherin蛋白、β-catenin蛋白、vimentin蛋白的表达来促进EMT,进而在乳腺癌的侵袭和转移过程发挥重要作用。     

上皮钙依赖粘附素相关分子在乳腺浸润性小叶癌和导管癌中的表达及意义

目的 探讨上皮钙依赖粘附素相关分子α-、β-、γ-catenin在乳腺浸润性小叶癌（ILC）和浸润性导管癌（IDC）中的表达及其意义。方法 采用免疫组织化学LSAB法检测了19例ILC和32例IDC组织中α-、β-、γ-catenin的表达,并根据阳性癌细胞占肿瘤细胞的比例进行半定量化分析和统计学x^2检验。结果 α-、β-、γ-catenin在19例ILC中表达缺失和明显减少的分别为15例（78.9%),10例（52.6%)和16例（84.2%),而在32例IDC癌组织中的表达缺失和明显减少为24例（75.0%),14例（43.8%)和26例(81.3%)例。另外,这3种蛋白在浸润性癌组织中表达强度弱于原位癌灶的表达强度。α-catenin和β-catenin在乳腺浸润性癌中的表达具有明显的正相关性,未发现α-、β-、γ-catenin在乳腺浸润性癌中的表达与有无伴有淋巴结转移病例之间的关系有统计学意义。结论 α-、β-、γ-catenin在乳腺ILC和IDC中表达均为明显缺失和减少,说明这些粘附分子在乳腺浸润性癌发生中确实丧失了其正常的细胞粘附功能。     

泛素羧基端水解酶L1在人类疾病发生发展中的调控作用

泛素-蛋白酶系统(ubiquitin proteasome system,UPS)在细胞分裂、细胞信号转导以及细胞程序死亡的过程中起到非常重要的作用.此系统主要是靠泛素化酶和去泛素化酶来实施对于目的蛋白的快速精确调控.其中,泛素羧基端水解酶L1 (ubiquitin carboxy-terminal hydrolase L1,UCH-L1)是去泛素化酶家族中的一个重要的分子,是由223个氨基酸组成的一类半胱氨酸水解酶,通过识另和裂解目标蛋白上羧基末端第76位甘氨酸,可把泛素分子从目标蛋白的多聚泛素化链上切割下来,阻止目标蛋白被UPS系统降解,从而对目标蛋白的降解代谢负向调控.由此而产生游离的泛素单体,则进一步循环参与下一个目标蛋白的泛素化代谢.UCH-L1是一个多功能的分子,除了去泛素化酶功能,还有稳定泛素单体,泛素连接酶及参与细胞骨架蛋白调控,细胞微管形成等多功能作用.     

Basal-like carcinoma of the breast: further evidence of the possibility that most metaplastic carcinomas may be actually basal-like carcinomas

Some investigators have previously suggested that basal-like carcinoma may consist of components of invasive ductal carcinoma, not otherwise specified, metaplastic carcinoma, and medullary carcinoma. We report here two cases of breast carcinoma showing basal cell/myoepithelial differentiation. The first case was a 58-year-old Japanese woman and the second case was a 39-year-old Japanese woman. The two tumors were composed of the proliferation of epithelial cells and/or spindle-or stellate-shaped cells on the background of mucinous materials. Additionally, chondroid matrix was observed in the metastatic lesion of the first case and the primary lesion of the second case. Immunohistochemically, epithelial neoplastic cells were positive for E-cadherin and cytokeratin CAM5.2, and epithelial and spindle-or stellate-shaped cells were positive for cytokeratins 5, 14, or 17, alpha-smooth muscle actin, S-100, and p63. Our results supply further evidence that most metaplastic carcinomas may be actually be basallike carcinomas.     

Carcinoma ex-pleomorphic adenoma of the breast. Report of three cases suggesting a relationship to metaplastic carcinoma of matrix-producing type

Three cases of carcinoma ex-pleomorphic adenoma of the breast are reported. Patients were 82, 60 and 56 years old and presented with a breast lump. All tumours showed areas of pleomorphic adenoma adjacent to typical areas of malignant transformation. These cases add to the spectrum of tumours shared by breast and salivary gland. The relationship between these neoplasms and metaplastic carcinoma of matrix-producing type is discussed.     

Clinical significance of NOB1 expression in breast infiltrating ductal carcinoma

Background: NIN/RPN Binding protein 1 homologue (NOBp1), encoded by NOB1 gene, was reported to play an essential role in the oncogenesis and prognosis of carcinomas. We conducted a study to reveal its expression and clinical significance in breast infiltrating ductal carcinoma. Methods: To explore the relationship between NOB1 expression and the clinical TNM (cTNM), 162 patients who undergone surgery were involved in the study. Compared to healthy tissues, abnormal localization and higher level of NOB1 in tumor cells was observed by Immunohistochemistry staining. Real-time PCR and western-blotting verified the up-regulation of NOB1 in carcinoma individuals. Results: A significant correlation between high level of NOB1 and the T stage, lymph node metastasis and cTNM was shown. Furthermore, patients with higher level of NOB1 predicted a declined overall survival (OS). Notably, multivariate analyses by Cox’s proportional hazard model revealed that expression of NOB1 was an independent prognostic factor in breast infiltrating ductal carcinoma. Conclusions: In summary, our present study clarify that the aberrant expression of NOB1 in breast infiltrating ductal carcinoma is possibly involved with tumorigenesis and development, and the NOB1 protein could act as a potential biomarker for prognosis assessment of breast infiltrating ductal carcinoma. Related mechanism is worthy of further investigation.     

Clinicopathologic features of the mixed epithelial and mesenchymal type metaplastic breast carcinoma with myoepithelial differentiation in a subset of six cases

Metaplastic carcinoma (MC) of the breast, consisting of epithelial and mixed epithelial-mesenchymal tumors, are extremely rare human neoplasms. They are mostly detected between the 5th and 7th decade and have an unfavorable prognosis. Therefore, it is of utmost important to find out the behavior and also the immunohistochemical (IHC) profile of these tumors. In the current study, the aim was to examine 6 cases of MC with detailed clinico-pathological variables of cancer, follow-up and IHC profile of several antigens. The following immunohistochemical markers were used: MNF116, vimentin, CD10, smooth muscle actin (SMA), estrogen/progesterone receptors and HER-2/neu. The mean age was 39.1 the mean size was 3.3 cm. 83% of the cases had spindle cell sarcoma-like areas. Two of six cases also had a chondrosarcoma-like component. The epithelial component was invasive ductal carcinoma in all. MNF116, vimentin, CD10, and SMA expressions were as follows: mesenchymal cells: 33%, 100%, 50%, 83%, epithelial cells: 100%, 50%, 33%, 0%. All were triple negative. 66.6% presented with the axillary lymph node metastases. The mean follow-up period was 51 months, 50% died of the disease. Two had distant metastases to the lung. Our series which only included mixed epithelial-mesenchymal type metaplastic carcinoma of the breast showed myoepithelial differentiation with a worse prognosis.     

Epithelial to mesenchymal transition in early stage endometrioid endometrial carcinoma

Epithelial to mesenchymal transition is thought to be implicated in tumor invasion and metastasis. To investigate its role in myometrial invasion, samples from 42 stage I (confined to the corpus) endometrioid endometrial carcinomas were analyzed. All E-cadherin repressors (SNAI1, SNAI2 (SLUG), ZEB1, HMGA2, and TWIST1) had a higher expression in endometrioid endometrial carcinomas than in normal endometrium (P < .0001), whereas CDH1 (E-cadherin gene) tended to be lower. In comparison with nonmyoinvasive (stage IA) tumors, those with deep myometrial invasion (stage IC) had increased messenger RNA expression of SLUG, ZEB1, and HMGA2 (P < .001). Furthermore, samples from the myoinvasive front of deeply invasive tumors had higher levels of SLUG, ZEB1, and HMGA2 than the corresponding superficial samples. Immunohistochemical analysis of these cases revealed that the decrease in E-cadherin was concordant with an increase in Snail and Twist protein expression. Trying to induce epithelial to mesenchymal transition in endometrioid endometrial carcinomas, we initially produced persistent activation of this pathway in Ishikawa cells. The cell line was infected with lentiviruses carrying the V600E mutation of BRAF, inducing loss of β-catenin, E-cadherin, and cytokeratin and increase in vimentin and Snail. These changes were mediated by ERK1/2 phosphorylation, which was also increased at the myoinvasive front. Furthermore, MEK1/2 inhibitor UO126 reversed the mesenchymal phenotype. Our findings suggest that epithelial to mesenchymal transition regulators are implicated in myometrial invasion of endometrioid endometrial carcinoma and may be potential therapeutic targets through the MAPK/ERK pathway.     

Vimentin expression in 98 breast cancers with medullary features and its prognostic significance

The expression of vimentin, as assessed by immunohistochemistry, has been evaluated in 69 medullary carcinomas of the breast: 28 typical medullary carcinomas (TMC), 41 atypical medullary carcinomas (AMC), and 29 invasive ductal carcinomas with subtle medullary features that, however, did not fulfil the strict criteria of TMC or AMC. Immunoreactivity of at least 10% of the component cells was found in 14 of the medullary carcinomas (5 out of 28 TMC, 9 out of 41 AMC whereas only 1 of the invasive ductal carcinomas was vimentinpositive. The patients were followed for 8–13 years. No difference in recurrence-free survival or overall survival could be documented between vimentin-positive and vimentin-negative carcinomas with medullary features. No biological significance could be established for vimentin labelling in these lesions.     

CD24 expression has a prognostic impact in breast carcinoma

We investigated the prognostic significance of BAG-1 and CD24 in invasive breast carcinomas. Seventy cases of invasive breast carcinoma were studied immunocytochemically for the expression of BAG-1 and CD24. The results were correlated with several prognostic parameters, including 5-year survival. Univariate analysis showed a significant correlation of BAG-1 and CD24 overall positive staining with several adverse prognostic parameters, such as increased stage (p<0.0001), tumor grade 3 (p=0.016 and p=0.02, respectively), positive lymph nodes (p<0.0001), and increased tumor size (p<0.0001). Similar results were found for BAG-1 nuclear staining, as well as for positive cytoplasmic CD24 expression. Both of our markers studied had a significant, negative effect on survival. Multivariate analysis further revealed an independent prognostic impact for CD24 overall staining. The results of our study showed that overall cytoplasmic and especially nuclear BAG-1 expression, as well as overall and cytoplasmic CD24 expression, correlates with adverse prognostic parameters. An independent prognostic value for overall CD24 staining was also demonstrated.     

Clinicopathological significance of ERCC1 expression in breast cancer

The excision repair cross-complementation 1 (ERCC1) enzyme plays an essential role in the nucleotide excision repair pathway and is associated with resistance to platinum-based chemotherapy in different types of cancer. The aim of the present study was to evaluate the clinicopathological significance of ERCC1 expression in breast cancer patients. We analyzed the immunohistochemical expression of ERCC1 in a tissue microarray from 135 primary breast carcinomas and correlated the immunohistochemical findings with clinicopathological factors and outcome data. ERCC1 expression analysis was available for 109 cases. In this group, 58 (53.2%) were positive for ERCC1. ERCC1-positive expression was correlated with smaller tumor size (P = 0.007) and with positivity for estrogen receptor (P = 0.040), but no correlation was found with other clinicopathological features. Although not statistically significant, triple negative breast cancers were more frequently negative for ERCC1 (61.5% of the cases) compared to the non-triple negative breast cancer cases (41.5%). In conclusion, ERCC1 expression correlated significantly with favorable prognostic factors, such as smaller tumor size and ER-positivity, suggesting a possible role for ERCC1 as a predictive and/or prognostic marker in breast cancer.     

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.     

Expression of Rsf-1, a chromatin-remodeling gene, in ovarian and breast carcinoma

Rsf-1 protein is a member of a chromatin-remodeling complex that plays an important role in regulating gene expression and cell proliferation. Our previous study showed that Rsf-1 was an amplified gene that participated in the development of ovarian serous carcinoma. To further elucidate the role of Rsf-1 in ovarian cancer, we studied Rsf-1 immunoreactivity in 294 ovarian tumors of various histologic types. Because the Rsf-1 amplicon overlaps an amplified region reported in breast cancer, we included 782 neoplastic and normal breast tissues for comparison. Immunohistochemistry was performed on tissue microarrays using a 4-tiered scoring system. Overexpression of Rsf-1 was defined as a nuclear immunointensity of 3+ to 4+ because of a strong correlation between 3+ and 4+ immunointensity and Rsf-1 gene amplification, based on our previous fluorescence in situ hybridization analysis. Rsf-1 overexpression was observed in 25% of high-grade ovarian serous carcinomas and in only rare cases (<7%) of low-grade ovarian serous, ovarian endometrioid, and invasive breast carcinomas but not in any ovarian serous borderline tumors, ovarian clear cell carcinomas, ovarian mucinous carcinomas, intraductal carcinomas of the breast, and normal ovaries and breast tissues. Thus, overexpression of Rsf-1 was significantly associated with high-grade ovarian serous carcinoma (P < .05), as compared with other types of ovarian tumors and breast carcinomas. Our results provide evidence that Rsf-1 expression is primarily confined to high-grade serous carcinoma, the most aggressive ovarian cancer. Because Rsf-1 overexpression occurs in only a small number of breast carcinomas, it is unlikely that Rsf-1 is a critical gene in the development of breast carcinoma.