Reduced PTEN expression is associated with poor outcome and angiogenesis in invasive ductal carcinoma of the breast.

Loss of PTEN expression has been associated with advanced stages of tumor. Tumor angiogenesis is involved in tumor progression. In breast cancer, a high frequency of mutations of the PTEN locus has been reported. However, the prognostic importance of PTEN expression and its correlation with angiogenesis in breast cancer have not been well established. Formalin-fixed, paraffin-embedded tissues from 99 women with a primary diagnosis of invasive ductal carcinoma were evaluated for PTEN expression by immunohistochemical methods. The microvessel density (MVD) was also studied by immunohistochemical labeling of endothelial cells with CD34 antibody. Computerized image analysis was used to evaluate MVD. Reduced PTEN expression was seen in 27.3% of invasive ductal carcinoma. The MVD ranged from 22.0 to 197.0, with a median value of 58.5 (65.4 +/- 27.9). Reduced PTEN expression correlated with lymph node status (P < 0.01), tumor grade (P < 0.05), and tumor-node-metastasis (TNM) stage (P < 0.05). There was a statistically significant correlation between reduced PTEN expression and increased MVD (P < 0.05). The mean MVD was higher in reduced PTEN-expressive tumors, irrespective of stage, compared with normal PTEN-expressive tumors with the same stage. On multivariate analysis, only TNM stage and reduced PTEN expression correlated with survival. Our results suggest that reduced PTEN expression may be an independent prognostic indicator in patients with invasive ductal carcinoma. PTEN loss may be associated with increased tumor angiogenesis.     

Expression of MT-1 MMP, MMP2, MMP9 and TIMP2 mRNAs in ductal carcinoma in situ and invasive ductal carcinoma of the breast

We investigated the expression of membrane type-1 (MT1)-MMP, MMP2, MMP9 and TIMP2 mRNAs and their roles in ductal carcinoma in situ (DCIS) and T1 and T2 invasive ductal carcinoma of the breast. We further compared these two types of carcinomas for differences in microvessel density, and expression of angiogenic factors and CD44std. MT1-MMP, MMP2, MMP9 and TIMP2 mRNA were expressed in both DCIS and invasive ductal carcinomas. Expression rates of MT1-MMP, MMP2, MMP9 and TIMP2 mRNAs were not statistically different between DCIS and invasive ductal carcinomas, nor did they differ statistically when grouped by tumor size, histologic grade or nuclear grade of invasive ductal carcinoma. Microvessel density and expression of VEGF and TGF-beta1 were not statistically different between DCIS and invasive ductal carcinoma. CD44std expression was significantly increased in DCIS compared to invasive ductal carcinoma (p < 0.05) and it was also significantly increased in lower clinical stage, histologic grade and nuclear grade of invasive ductal carcinoma (p < 0.05). Axillary node metastasis was significantly correlated with MT1-MMP mRNA, VEGF and TGF-beta1 expression (p < 0.05) and MT1-MMP mRNA was positively correlated with VEGF expression and TIMP2 mRNA (p < 0.05). In summary, patterns of MMP mRNA expression in DCIS and invasive ductal carcinoma suggest that the invasive potential of breast carcinoma is already achieved before morphologically overt invasive growth is observed. As MT1-MMP mRNA expression is significantly correlated with axillary nodal metastasis, it may be useful as a prognostic indicator of invasive ductal carcinoma. Considering the positive correlation of MT1-MMP mRNA and TIMP2mRNA expression, our finding supports a role for TIMP2 in tumor growth, as well as the utility of CD44std as a prognostic indicator of breast cancer.     

HER-2、HIF-1a、GLUT-1及VEGF表达在乳腺浸润性导管癌淋巴结转移中作用

目的 研究人表皮生长因子2(HER-2)与乏氧诱导因子1a(HIF-1a)、葡萄糖转运蛋白1(GLUT-1)、血管内皮生长因子(VEGF)在乳腺浸润性导管癌组织中的表达,探讨它们在乳腺浸润性导管癌淋巴结转移中的作用.方法 应用免疫组化SP法检测80例乳腺浸润性导管癌(腋淋巴结转移者36例、无腋淋巴结转移者44例)的HER-2、HIF-1a、GLUT-1及VEGF的表达情况,统计分析HER-2、HIF-1a、GLUT-1及VEGF与乳腺浸润性导管癌淋巴结转移的作用及其相关性.结果 HER-2、HIF-1a、GLUT-1及VEGF在乳腺浸润性导管癌腋淋巴结转移组比无腋淋巴结转移组明显高表达(P<0.05);HER-2与HIF-1a的表达呈正相关(r=0.411,P=0.000);HIF-1a与GLUT-1的表达呈正相关(r=0.389,P=0.000);HIF-1a与VEGF的表达呈正相关(r=0.425,P=0.000).结论 HER-2、HIF-1a、GLUT-1及VEGF在乳腺浸润性导管癌淋巴结转移中发挥重要作用,HER-2可能通过HIF-1a对GLUT-1、VEGF进行调控.     

Expression of cell adhesion molecules, CD44s and E-cadherin, and microvessel density in invasive micropapillary carcinoma of the breast

AIMS: Invasive micropapillary carcinoma (IMPC) is a rare variant of ductal carcinoma of the breast and is characterized by high metastatic potential and an aggressive clinical course. This tumour is hence ideal for studying the mechanism underlying tumour biological behaviour, especially metastasis. Cell adhesion molecules, such as CD44 and E-cadherin (Ecad), and angiogenesis are considered important in the invasion and metastasis of tumours. METHODS AND RESULTS: We immunohistochemically analysed 23 IMPCs for expression of a standard form of CD44 (CD44s), Ecad, and CD34 to measure microvessel density (MVD). Results are compared with the changes observed in 23 tubular carcinomas (TCs), another variant of ductal carcinoma that rarely metastasizes. Evaluation of haematoxylin and eosin (H&E) sections showed a higher prevalence of lymph-vascular invasion (19/23, 83%) and regional lymph node involvement (12/15, 80%) in IMPCs; whereas no lymph-vascular invasion or lymph node metastasis was identified in TCs. Loss or reduction of CD44s immunoreactivity was significantly frequent in IMPC (39%) compared with TC (4%) (P = 0.0098), and was associated with positive axillary lymph nodes and lymph-vascular invasion. All cases of IMPC and TC strongly expressed Ecad. MVD (in five 200x fields) was significantly higher in IMPC (88 +/- 37) than in TC (57 +/- 16) (P = 0.001). In the IMPC group, MDV was higher in cases with positive lymph node(s) (P = 0.048), and cases with loss or reduction of CD44s expression (P = 0.011). The same trend was also demonstrated in cases with lymph-vascular invasion (P = 0.077). Moreover, the vessels in IMPC had much smaller calibres with thinner walls than those in TC. CONCLUSIONS: Loss of the CD44 adhesion molecule and high MVD may play a significant role in the high incidence of lymph-vascular permeation and metastasis in IMPC.     

血管内皮生长因子,微血管密度与乳腺癌淋巴结转移及预后？…

目的　探讨血管内皮生长因子 (VEGF)、微血管密度 (MVD)与乳腺癌淋巴结转移和预后的关系。方法　应用逆转录 聚合酶链反应 (RT PCR)与免疫组织化学SP法 ,检测 92例乳腺癌、12例癌旁组织V组织VEGF表达、MVD以及 2 1例乳腺癌、12例癌旁组织VEGFmRNA的表达。结果　乳腺癌组织 ,VEGF12 1(1.16 %± 0 1% )和VEGF165(1.0 1%± 0 .1% )表达高于癌旁组织 (0 .96 %± 0 .14% )、(0 .88%± 0 .1% ) ,P <0 .0 5～ 0 .0 1。此外 ,MVD与VEGF表达具有显著的正相关关系 (r =0 .70 2 ,P <0 .0 1)。VEGF表达和MVD与乳腺癌淋巴结转移、肿瘤复发关系密切 (P <0 .0 5～ 0 .0 1)。VEGF高表达组和高MVD组的无复发存活时间低于VEGF低表达组和低MVD组 ,差异具有非常显著性 (P <0 0 1)。结论　VEGF与乳腺癌血管生成密切相关 ;VEGF和MVD表达的增高对乳腺癌淋巴结转移、肿瘤复发有促进作用 ;VEGF和MVD对乳腺癌患者的无复发存活时间能起到预测作用     

Decline in the expression of the serine proteinase inhibitor maspin is associated with tumour progression in ductal carcinomas of the breast

Maspin is an inhibitor of serine proteinases with tumour suppressor activity. Its expression appears to be reduced in advanced stages of breast cancer. A large series of archival breast tissue specimens has been examined, including normal glands (n=7), fibrocystic change (n=22), ductal carcinoma in situ (DCIS, n=12), infiltrating carcinomas (n=128) and their lymph node metastases (n=65), using a specific monoclonal antibody. Myoepithelium invariably showed strong maspin expression. In epithelial cells, the strongest expression was found in normal breast and fibrocystic change. A significant stepwise decrease in maspin expression (p<0.0001) occurred in the sequence DCIS - invasive cancer - lymph node metastasis. However, a subset of infiltrating carcinomas showed strong maspin expression, significantly associated with a lower rate of lymph node metastasis at the time of diagnosis (p<0.01). This was independent of tumour size and grade. The in vivo observations presented here are in keeping with data obtained in prior in vitro experiments. Maspin emerges as an indicator of tumour progression and metastatic potential, and might be exploited to predict breast cancer prognosis. According to in vitro data, its tumour suppressor activity is likely to involve both the modulation of cell motility/invasiveness and the inhibition of angiogenesis.     

Angiogenic potential of ductal carcinoma in situ (DCIS) of human breast

AIMS: Comedo carcinoma is generally regarded as the subtype of ductal carcinoma in situ (DCIS) most likely to progress to invasive carcinoma. Increased angiogenesis could be associated with an enhanced risk of progression and might therefore be a marker of poor prognosis, as can be demonstrated for invasive breast tumours. Therefore, the present study investigates the correlations between the expression of oncoproteins (HER2, HER1/EGFR), angiogenic growth factors (VEGF and PD-ECGF/TP) and microvessel density (MVD) in DCIS. METHODS AND RESULTS: Forty-six breast cancer specimens of DCIS were tested immunohistochemically for the expression of angiogenic factors and oncoproteins. Different vascular distribution patterns of DCIS were examined semiquantitatively. Our results showed a significantly inverse correlation between HER1/EGFR and comedo-type DCIS (P = 0.048), but HER1/EGFR expression seemed to be independent of HER2 overexpression. VEGF expression was significantly associated with endoglin expression (P = 0.031) and the cuffing phenomenon (P = 0.017). CONCLUSIONS: The significantly inverse correlation between HER1/EGFR and comedo-type DCIS and the observation that VEGF and the other angiogenic factors tested are independent of HER2 overexpression, suggest that progression of comedo-type DCIS and angiogenesis in breast carcinoma are not regulated via the HER1/EGFR or HER2 pathway.     

血管内皮生长因子C和nm23表达与微血管密度及宫颈癌转移的关系

目的探讨血管内皮生长因子-C(vascular endothelial growth factor-C,VEGF-C)和nm23(non-metastasis23)表达与微血管密度(microvessel density,MVD)及宫颈癌转移的关系。方法采用免疫组化SABC法检测16例正常宫颈上皮及68例宫颈癌中VEGF-C、nm23的表达。并用CD105标记新生血管内皮细胞,计算肿瘤内MVD。结果VEGF-C在宫颈癌组织中的阳性表达率显著高于正常组织(P<0.01),淋巴结转移组VEGF-C阳性率高于无淋巴结转移组(P<0.05),VEGF-C表达强度与MVD呈正相关(P<0.05)。nm23蛋白表达率显著低于正常组织(P<0.01),淋巴结转移组nm23阳性率低于无淋巴结转移组(P<0.05)。nm23在宫颈癌中的表达与VEGF-C呈负相关(P<0.01)。结论宫颈癌组织VEGF-C呈高表达、nm23呈低表达,可能在宫颈癌血管生长、肿瘤浸润转移过程中起重要作用。检测宫颈癌中VEGF-C、nm23表达对进一步了解宫颈癌局部血管生成情况及判断预后有一定的应用价值。     

乳腺癌组织Livin和PTEN表达与肿瘤血管生成的相关性

目的:研究乳腺癌组织中凋亡抑制蛋白Livin和抑癌基因PTEN的表达与微血管密度(MVD)的关系,探讨乳腺癌血管生成的影响机制。方法:应用免疫组化Elivision法检测90例乳腺癌和30例乳腺纤维腺瘤组织中Livin、PTEN、VEGF的表达和CD34标记的MVD值,分析Livin和PTEN表达与乳腺癌血管生成及侵袭转移的关系。结果:在90例乳腺癌中Livin、PTEN和VEGF表达阳性率分别为54.4%、48.9%和61.1%,MVD为(30.81±11.29)个/HPF,与良性对照组比较均有显著差异(P<0.01);Livin阳性表达与乳腺癌肿瘤大小、临床分期、MVD值及VEGF表达呈正相关(P<0.05),与年龄、病理分级、淋巴结转移未见显著相关(P>0.05);PTEN表达与乳腺癌淋巴结转移、临床分期和MVD呈负相关(P<0.05),与VEGF表达、年龄、肿瘤大小、病理分级未见显著相关(P>0.05)。结论:Livin和PTEN在乳腺癌的血管生成及发生发展过程中分别起促进和抑制作用,Livin的促血管生成作用可能与其上调VEGF的表达有关。     

Loss of expression of transforming growth factor beta type II receptor correlates with high tumour grade in human breast in-situ and invasive carcinomas

AIMS: Loss of transforming growth factor beta type II receptor (TGFbeta-RII) expression has been associated with resistance to TGFbeta-mediated inhibition of cell proliferation and tumour progression. We investigated whether the expression of TGFbeta-RII is related to the progression of human breast cancer and whether there is a correlation between TGFbeta-RII expression and phenotypic markers of biological aggressiveness. METHODS AND RESULTS: Immunohistochemical methods were used to detect TGFbeta-RII in archival breast samples including benign proliferative lesions, ductal carcinoma in situ (DCIS) and invasive mammary carcinomas (IMC). Neoplastic cells showed reduced expression of TGFbeta-RII in comparison to the normal breast tissue and benign lesions. There was a significant inverse correlation between loss of TGFbeta-RII expression and tumour grade within both DCIS (P = 0.004) and IMC (P = 0.001) groups. There was an inverse correlation between TGFbeta-RII expression and both mitotic count (P = 0.001) and clinical stage (P = 0.004). Oestrogen receptor (P = 0.07) and lymph node status (P = 0.10) were not significantly associated with TGFbeta-RII expression. CONCLUSIONS: These data indicate that decreased expression of TGFbeta-RII may contribute to breast cancer progression and is related to a more aggressive phenotype in both in-situ and invasive carcinomas.     

Hypercholesterolemia impairs angiogenesis in patients with breast carcinoma and, therefore, lowers the risk of metastases

Our aim was to study the effect of hypercholesterolemia on angiogenesis induced by breast carcinoma. Of 51 patients with invasive ductal carcinoma, 28 had hypercholesterolemia and 23 had normocholesterolemia. The intratumoral microvessel density (MVD) was evaluated by using anti-CD31 antibody. The expression of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) on endothelial and tumor cells was examined and graded semiquantitatively. Patients with normocholesterolemia had a higher MVD (76.4 +/- 8.2) than those with hypercholesterolemia (54.6 +/- 5.1) (P < .01). The risks of recurrence and distant metastasis were higher in patients with normocholesterolemia than in patients with hypercholesterolemia (P < .01). Patients with hypercholesterolemia showed lower expression of endothelial VEGF and bFGF than patients with normocholesterolemia (P < .05 and P < .01, respectively). In addition, tumoral bFGF and VEGF expression showed negative correlation with the presence of hypercholesterolemia (P < .01). We suggest that hypercholesterolemia impairs angiogenesis by suppressing endothelial and tumoral bFGF and VEGF expression and, therefore, lowers the risk of metastases in cases of invasive breast carcinoma.     

Coexpression of heparanase, basic fibroblast growth factor and vascular endothelial growth factor in human esophageal carcinomas

Heparan sulfate (HS), which is degraded by heparanase, plays an important role in cell adhesion, insolubility of the extracellular matrix (ECM) and as a reservoir for various growth factors such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). In the present study, we examined the immunohistochemical expression of heparanase, bFGF and VEGF, and evaluated the correlation between their expression and microvessel density (MVD) in human esophageal carcinomas. Heparanase, bFGF and VEGF were immunolocalized predominantly to the carcinoma cells, but they were also localized to the endothelial cells of microvessels near the carcinoma cell nests. In carcinomas with invasion of the muscular layer or adventitia, heparanase staining was stronger at the invasive areas of carcinomas than the intraepithelial spread. Expression of heparanase and bFGF and the degree of MVD were associated with tumor invasion, lymph node metastasis and pathological stages. Cases with positive staining for heparanase, bFGF or VEGF tended to have a higher MVD than those without staining, and carcinomas with concomitant expression of heparanase, bFGF and VEGF showed the highest MVD. The level of heparanase mRNA expression was directly correlated with the MVD. In addition, heparanase-positive cases had a higher positive ratio of bFGF and VEGF compared with the heparanase-negative cases. These data suggest the possibility that heparanase may contribute to not only cancer cell invasion but also angiogenesis probably through degradation of HS in the ECM and release of bFGF and VEGF from the HS-containing ECM.     

Correlation between vascular endothelial growth factor,angiogenesis, and tumor-associated macrophages in invasive ductal breast carcinoma

Angiogenic and anti-angiogenic factors, secreted by tumor, inflammatory, and stromal cells play an important role in regulation of neovascularization. Among the most important of these is vascular endothelial growth factor (VEGF), a specific mitogen for endothelium, which increases vascular permeability and induces proteolytic enzymes necessary for vascular remodeling. Tumor-associated macrophages (TAMs) can express complex functions related to tumor biology, including growth, proliferative rate, stroma formation and dissolution, and neovascularization. The aim of this study was to define, using immunohistochemical analysis, the microvessel density (MVD), VEGF expression, and TAMs level in 97 human invasive ductal breast carcinomas not otherwise specified (NOS), investigate a possible relationship between them and then correlate their values with tumor grade, mitotic activity index (MAI), tumor size and lymph-node status. Statistical analysis showed a strong positive relationship between MVD and VEGF expression ( P<0.001). Furthermore, both MVD and VEGF expression were significantly correlated with tumor grade and lymph-node status, and TAMs infiltration with MAI. TAM level showed a significant positive connection with VEGF expression and MVD. These in situ observations suggest that VEGF stimulates angiogenesis in human invasive ductal breast carcinoma NOS and attracts macrophages to the tumor locus, which then may be involved in angiogenesis promotion. The expression of this angiogenic molecule, and MVD and TAM level, can provide additional prognostic significance and help in the identification of patients who need postoperative adjuvant therapy.     

KPNA2 protein expression in invasive breast carcinoma and matched peritumoral ductal carcinoma in situ

The aim of this study was to evaluate protein expression of Karyopherin alpha 2 (KPNA2) in invasive breast cancer and matched ductal carcinoma in situ (DCIS) and to correlate it with clinicopathological data, including patient survival. KPNA2 protein expression was assessed by immunohistochemistry in breast tissue samples, containing invasive carcinomas, DCIS, and adjacent histologically benign breast tissues. A polyclonal goat KPNA2 antibody was used for immunostaining of 83 clinicopathologically characterized cases. For statistical analysis, staining of at least 10% of nuclei was considered KPNA2 positive. Immunohistochemical detection of KPNA2 in invasive carcinoma showed a significant correlation with higher tumor stage, positive lymph node status, higher tumor grade, and negative ER status. Concordantly, KPNA2-positive tumors (31.3%) showed significantly shorter disease-free survival times (69 months vs 118 months; p = 0.007). KPNA2 protein expression was also detected in DCIS (21.3%) adjacent to invasive tumor and correlated with nuclear grade (p = 0.013). Expression of KPNA2 in invasive breast cancer correlates with conventional prognostic parameters and shorter disease-free survival. Additionally, KPNA2 is overexpressed in DCIS, particularly high grade lesions, which emphasizes its potential role in carcinogenesis of invasive breast carcinomas.     

乳腺癌中E-cadherin的表达及其临床病理意义

目的 探讨上皮钙黏附表（E-cadherin，E-cad）与乳腺癌临床病理和生物学行为的关系。方法 用免疫组化S-P法检测乳腺浸润性导管癌和浸润性小叶癌中E-cad的表达情况及其与淋巴结转移，ER-PR表达水平的相关性。结果 乳腺浸润性导管癌E-cad表达高于浸润性小叶瘤，有淋巴结转移者E-cad表达低于无转移者，E-cad高表达的乳腺浸润性导管癌及浸润性小肾癌中均与ER-PR表达水平成正相关。结论 E-cad中作为乳腺癌分类、转移潜能和预后判断的参考指标。     

Amplification of Her-2/neu gene in Her-2/neu-overexpressing and -nonexpressing breast carcinomas and their synchronous benign, premalignant, and metastatic lesions detected by FISH in archival material.

Amplification of Her-2/neu in breast carcinoma is associated with poor prognosis, short disease-free interval, and short survival time in both node-negative and -positive patients. Little is known about the starting point of amplification of Her-2/neu and how it progresses from benign to malignant breast lesions. We attempted to address these questions by evaluating amplification of Her-2/neu in benign, premalignant, and malignant lesions using fluorescence in situ hybridization (FISH). Twenty-six patients with Her-2/neu-overexpressing invasive ductal carcinomas (as judged by strong immunoreactivity with Her-2/neu antibody) and coexisting lesions of ductal hyperplasia (DH), atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) in the vicinity of the invasive tumor (as judged by review of the hematoxylin and eosin-stained sections), as well as metastatic carcinoma in axillary lymph nodes (mets) were selected for this study. In the primary carcinomas, a close relationship was present between overexpression as detected by immunohistochemistry (IHC) and amplification as demonstrated by FISH (85% concordance). Among these patients, amplification of Her-2/neu in ADH was demonstrated in 7 of 13 cases with ADH, and in DCIS, in 21 of 22 cases with DCIS. There was no amplification in DH or normal ductal epithelium. Significantly, in all 12 patients with synchronous positive axillary lymph nodes, there was concordant amplification of Her-2/neu in the primary and metastatic carcinoma. Amplification was consistent in multifocal metastases, despite morphological heterogeneity in some patients. Amplification ratios increased from ADH to DCIS to invasive carcinoma (P <.01, ADH versus DCIS; P <.05, DCIS versus invasive cancer), but there was no difference in amplification ratios between primary cancers and synchronous axillary metastases (P >.05). We also evaluated Her-2/neu amplification in 21 patients without Her-2/neu overexpression in their primary carcinomas (as judged by absent immunoreactivity with Her-2/neu antibody). Three showed amplification in both primary and metastatic lesions, with a low amplification ratio (approximately 2). One patient had amplification in the primary tumor but not in an axillary metastasis. Two patients exhibited slight amplification in the metastatic carcinoma (ratios 1.6 and 2), but not in their primary cancers. This FISH study indicates that amplification of Her-2/neu can emerge de novo in any stage of the disease process, from ADH to metastatic lesions, but most often appears first in ADH or DCIS. The degree of Her-2/neu amplification increases with progression to invasive carcinoma, there being no further increase in synchronous metastasis. Our data suggest that amplification of Her-2/neu appears to be mainly involved in initiation of breast oncogenesis and that its role in progression of breast cancers is uncertain.     

Loss of expression of the PTEN gene protein product is associated with poor outcome in breast cancer.

INTRODUCTION: The PTEN gene, a candidate tumor suppressor, is localized to chromosome 10q23 and shares extensive homology with cytoskeletal proteins auxilin and tensin. A high frequency of mutations at the PTEN locus has been described in a variety of neoplasms including breast cancer. However, the role of PTEN alternations and its association with outcome variables in breast neoplasia is not well established. DESIGN: Formalin-fixed paraffin embedded tissues from 151 women (mean age 62 years, range 26-98) with primary diagnosis of invasive breast cancer were evaluated for PTEN protein expression by automated immunohistochemical methods. Slides were scored semi-quantitatively based on staining intensity and distribution, and results were compared with clinical pathologic parameters. The mean follow-up was 56 months (range 1-169). RESULTS: Seventy-three (48%) of 151 breast tumors had loss of PTEN protein expression. On univariate analysis, loss of PTEN expression (P =.034), stage (P <.0001), node positive (P <.0001), and tumor grade (P =.002) were associated with disease-related death. Loss of PTEN expression also predicted lymph node metastasis (P <.0001), and correlated with loss of estrogen receptor staining (P =.040). Loss of PTEN did not correlate with stage, tumor grade, disease recurrence, or loss of progesterone receptor [although a trend was seen (P =.092). On multivariate analysis, stage (P <.0001), lymph node metastasis (P <.0001), and tumor grade (P =.002) correlated with survival. CONCLUSION: Loss of PTEN protein expression occurs commonly in breast cancer and correlates with disease related death, lymph node metastasis, and loss of estrogen receptor staining. Our results support the proposed role of PTEN as a candidate tumor suppressor in breast cancer and suggest a need for further study of this marker.     

Expression of CD44s, CD44v6, and hyaluronan across the spectrum of normal-hyperplasia-carcinoma in breast.

BACKGROUND: The interaction between transmembrane receptors on epithelial tumor cells and the surrounding extracellular matrix molecules is important in tumor progression and metastasis. This interaction is best exemplified by the relationship of the receptor CD44 and the extracellular matrix component hyaluronan (HA). This study seeks to evaluate the expression and the correlation of CD44s, CD44v6, and HA in normal, hyperplastic, and malignant breast epithelium and stroma. MATERIALS AND METHODS: Archival paraffin-embedded tissue from cases of normal breast tissue (n=10), intraductal hyperplasia without atypia (n=13), ductal carcinoma in situ (DCIS) (n=24), stage I infiltrating ductal carcinoma (n=28), stage II infiltrating ductal carcinoma (n=31), and their corresponding positive lymph nodes were retrieved from the surgical pathology files. Tissue sections were evaluated for the expression of CD44s, CD44v6, and HA in the epithelial and stromal cells by immunohistochemistry. RESULTS: Ductal epithelial cells and myoepithelial cells expressed CD44s in all cases of normal and benign breast tissue. The expression of CD44s in breast epithelium progressively decreased with increasing deviation from normal histology: 83% in DCIS, 46% in stage I ductal carcinoma and 26% in stage II ductal carcinoma. The reverse trend was observed for CD44v6 in ductal epithelium: 0% in normal breast, 15% in intraductal hyperplasia, 100% in DCIS, 82% in stage I infiltrating ductal carcinoma, 94% in stage II carcinoma, and 100% of metastatic carcinoma in the lymph nodes. HA was noted exclusively in the stroma but not in the epithelial cells. HA was faintly expressed in the intralobular stroma of normal breast tissue, confined to a narrow faint band adjacent to intraductal hyperplasia and localized to a broad well-defined band around DCIS. Stromal HA staining was more diffuse and intense in infiltrating carcinomas and was particularly pronounced surrounding the metastatic deposits in lymph nodes. CONCLUSIONS: This study demonstrates decreased expression of CD44s accompanied by increased expression of CD44v6 and increased stromal HA in breast cancer. These findings suggest that CD44s, CD44v6, and HA play complementary roles in the development and progression of breast cancer.     

Prognostic significance of claudin expression changes in breast cancer with regional lymph node metastasis

Adherent and tight junction molecules have been described to contribute to carcinogenesis and tumor progression. Additionally, the group of claudin-low tumors have recently been identified as a molecular subgroup of breast carcinoma. In our study, we examined the expression pattern of claudins, beta-catenin and E-cadherin in invasive ductal (IDCs) and lobular (ILCs) carcinomas and their corresponding lymph node metastases (LNMs). Tissue microarrays of 97 breast samples (60 invasive ductal carcinomas, 37 invasive lobular carcinomas) and their corresponding LNMs have been analyzed immunohistochemically for claudin-1, -2, -3, -4, -5, -7, beta-catenin and E-cadherin expression. The stained slides were digitalized with a slide scanner and the reactions were evaluated semiquantitatively. When compared to LNMs, in the IDC group beta-catenin and claudin-2, -3, -4 and -7 protein expression showed different pattern while claudin-1, -2, -3, -4 and -7 were differently expressed in the ILC group. Lymph node metastases developed a notable increase of claudin-5 expression in both groups. Decrease or loss of claudin-1 and expression of claudin-4 in lymph node metastases correlated with reduced disease-free survival in our patients. According to our observations, the expression of epithelial junctional molecules, especially claudins, is different in primary breast carcinomas compared to their lymph node metastases as demonstrated by immunohistochemistry. Loss of claudin junctional molecules might contribute to tumor progression, and certain claudin expression pattern might be of prognostic relevance.     

宫颈癌COX-2、MMP-9和CD105表达与肿瘤血管生成及侵袭转移的关系

目的探讨环氧合酶-2(cyclooxygenase,COX-2)、基质金属蛋白酶-9(matrix metalloproteinase-9,MMP-9)在宫颈癌局部肿瘤血管生成及肿瘤侵袭转移过程中的作用。方法采用免疫组化SP法检测32例正常宫颈上皮及68例宫颈癌中COX-2、MMP-9的表达。并用CD105标记新生血管内皮细胞,计算肿瘤内微血管密度(microvascular density,MVD)。结果COX-2、MMP-9在宫颈癌组织中的阳性表达率均显著高于正常宫颈上皮中的表达(P<0.01)。COX-2、MMP-9阳性组的MVD均显著高于COX-2、MMP-9阴性组(P<0.01),淋巴结转移组COX-2、MMP-9阳性率均高于无淋巴结转移组(P<0.05)。结论COX-2、MMP-9阳性表达可能在宫颈癌血管生成和侵袭转移中起重要作用,两者在宫颈癌血管生成中可能具有协同作用。检测宫颈癌中COX-2、MMP-9表达对进一步了解宫颈癌局部血管生成情况及判断预后有一定的应用价值。