The polycomb group protein enhancer of zeste homologue 2 (EZH2) has been linked to invasive properties of aggressive breast cancer. In this report, tissue microarray analysis of 190 breast carcinomas from a nested case-control study shows that EZH2 is significantly associated with interval breast cancers. Further, a strong relationship was found with tumor cell proliferation (by Ki-67 expression), locally advanced disease, metastasis at presentation, markers of the basal epithelial phenotype (positivity for cytokeratin 5/6 or P-cadherin), and p53 status. EZH2 expression was also significantly associated with glomeruloid microvascular proliferation, an aggressive angiogenic phenotype. For prediction of aggressive disease (any event of locally advanced disease, lymph node spread, or distant spread), EZH2 was the only variable of significance in multivariate analysis, whereas no additional information was given by Ki-67. Although EZH2 expression was significant in univariate survival analysis, only tumor cell proliferation and lymph node status were significant in the final multivariate model. In conclusion, our findings indicate an important relationship not only between EZH2 and markers of tumor cell proliferation but also with aggressive disease. These findings might be practically important and relevant because the polycomb group proteins have recently been suggested as candidates for targeted therapy.Progression of breast cancer is a significant clinical problem and there is a need for novel treatment strategies. Although multiple prognostic factors have been reported, few markers, like c-erbB-2 status (Her2; ref. 1), have practical value as response predictors for targeted therapy (2). The enhancer of zeste homologue 2 (EZH2) is a member of the polycomb group of genes and has been involved in cell cycle regulation, and polycomb group proteins were recently suggested as candidates for targeted treatment (3). In human tumors, expression of EZH2 was first associated with hormone refractory and aggressive prostate cancer (4). In breast cancer, Kleer et al. (5) showed that EZH2 expression was increased in malignant tumors and promoted anchorage-independent and invasive growth in vitro, whereas proliferation was not significantly enhanced. EZH2 expression was further associated with increased tumor diameter, negative estrogen receptor (ER) and progesterone receptor (PR) status, and advanced stage of disease. Reduced patient survival was significantly predicted by EZH2 positivity in a subgroup of 194 cases. In a different study, Raaphorst et al. (6) found that EZH2 expression was associated with poorly differentiated and invasive breast cancers, whereas no clear relationship with proliferation was found. In this study, there was no prognostic effect of EZH2 expression.EZH2 is regulated by E2F transcription factors, which are liberated by retinoblastoma protein phosphorylation (7,8). Activated p53 down-regulates the EZH2 gene through repression of its promoter (9). Recently published cDNA microarray data i...

BACKGROUND: Putative breast cancer stem cells might express surface markers such as aldehyde dehydrogenase 1 (ALDH1) and BMI-1 proteins. The aim of this study was to explore the expression of these proteins in breast cancers from an African population and their associations with the basal-like phenotype (BLP) and other molecular characteristics. METHODS: We analysed 192 paraffin-embedded breast carcinoma samples by tissue microarrays and immunohistochemical methods. RESULTS: In total, 88 tumours (48%) expressed ALDH1, whereas 46 (25%) expressed BMI-1 protein. Expression of ALDH1 was associated with high histological grade (Po0.0005), high mitotic count (Po0.0005), high nuclear grade (Po0.0005), oestrogen receptor (ER) negativity (Po0.0005), progesterone receptor (PR) negativity (P ¼ 0.009), p53 expression (P ¼ 0.034), cytokeratin 5/6 positivity (P ¼ 0.008), epidermal growth factor receptor (EGFR) expression (P ¼ 0.015) and the BLP (Po0.0005), whereas it was inversely associated with BMI-1 staining (P ¼ 0.009). On the other hand, BMI-1 expression was associated with low histological grade (P ¼ 0.004) and ER positivity (P ¼ 0.001). CONCLUSION: There was a high prevalence of ALDH1 expression among breast carcinomas and associations with basal markers and features of aggressive tumours. Studies are required to elucidate the importance of these findings for improved understanding of breast cancer biology.

Introduction Existing methods to detect breast cancer in asymptomatic patients have limitations, and there is a need to develop more accurate and convenient methods. In this study, we investigated whether early detection of breast cancer is possible by analyzing gene-expression patterns in peripheral blood cells.

Purpose: BRCA1-related breast cancer frequently has a basal epithelial phenotype, and P-cadherin is a basal marker. We undertook a detailed evaluation of the relationship among P-cadherin, prognostic markers in breast cancer, and outcome. Experimental Design: This study was restricted to 292 cases of first primary invasive breast cancer diagnosed in Ashkenazi Jewish women between 1980 and 1995. All available blocks were stained for P-cadherin, and 261 were included in the final statistical analyses, including 27 germ line BRCA1 mutation carriers and 8 BRCA2 mutation carriers. Descriptive analyses were done followed by survival analyses and a Poisson regression analysis. Results: P-cadherin was present in 80 of the 261breast cancers (31%) and was more frequently present in tumors that have a basal epithelial phenotype [i.e., high-grade, estrogen receptor^and KIP1 (p27 Kip1)^negative tumors, with expression of cytokeratin 5/6, cyclin E,TP53, and presence of BRCA1 mutations and vascular nests (all P < 0.001)]. In a univariate survival model, expression of P-cadherin was associated with a relative risk (RR) of death from breast cancer at a 10-year follow-up of 2.9 (95% confidence interval, 1.8-4.7; P < 0.0001) and was a predictor of poor univariate survival in both lymph node^negative and^positive breast cancers. In a multivariate analysis, the effect of P-cadherin levels was not independent of other basal-related markers. Multivariable interaction modeling showed that P-cadherin positivity was highly predictive of a poor prognosis in small, node-negative breast cancers (RR, 7.1; P = 0.006). Conclusions: P-cadherin is a marker for basal-like breast cancers and is strongly associated with the presence of a BRCA1 mutation. It is an adverse prognostic factor, particularly in small, node-negative breast cancers.