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Abstract: Recently it has been shown that the genome organizer SATB1 plays an important role in breast cancer progression and predicts a poor prognosis. However its prognostic value compared to markers as the estrogen receptor is currently unclear. The expression levels of SATB1 mRNA from Affymetrix microarray in a cohort of 2058 breast cancer samples and its prognostic impact were analyzed. There was no significant difference in disease-free survival among ER negative cancers but instead a benefit for high SATB1 expression among ER positive tumors (p = 0.042). However, even in ER positive cancer no independent prognostic value in multivariate analysis with standard parameters was observed. Thus the use of SATB1 as target or prognostic marker for breast cancer should be viewed with caution and a possible confounding effect of the estrogen receptor status of the tumor should be taken into account when analysing new markers as SATB1. [Copyright &y& Elsevier]

Background: Proteomic analysis has become an effective tool in breast cancer research. In this study, we applied the new gel-free tandem mass tag (TMT) reference method for the first time in breast cancer. Materials and Methods: Proteomic analysis was used to compare 10 estrogen receptor (ER)-positive and 10 ER-negative samples. The results of the proteomic approach were validated by Western blot, immunohistochemistry and gene expression analysis. Results: 17 proteins with significant differences in expression were identified. 13 proteins were overexpressed in ER-negative tumors and 4 were overexpressed in ER-positive samples. All these proteins were characterized by relatively high cellular abundance. Conclusions: Our results demonstrate that the gel-free TMT approach allows the quantification of differences in protein expression levels. Further improvement of the sensitivity by subfractionation of the tissue should allow also the identification of low-abundance proteins and might lead to the use of this method in breast cancer research. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Sphingolipids are bioactive lipids implicated in apoptosis, cell survival and proliferation. We analyzed the prognostic value of enzymes from sphingolipid metabolism in breast cancer. Differences in expression of ceramide galactosyl transferase (UGT8), ceramide kinase (CERK), and Ganglioside GD3-Synthase (ST8SIA1) in breast cancer cells were investigated by using microarray data of 1,581 tumor samples. UGT8, CERK, and ST8SIA1 were associated with poor pathohistological grading ( P < 0.001). High CERK expression was correlated with ErbB2 status ( P = 0.006). Among ER positive breast cancers a significant worse prognosis for patients with tumors showing low ST8SIA1 and UGT8 expression was observed. In the ER negative subgroup those samples with high CERK expression displayed a worse prognosis. In a multivariate analysis only ST8SIA1 and tumor size remained significant. Our experiments reveal that expression of enzymes from the sphingolipid metabolism has prognostic implications in breast cancer. [ABSTRACT FROM AUTHOR]

Multidrug resistance (MDR) has been linked to sphingolipid metabolism and preclinical data ascribe glucosylceramide synthase (GCS) a major role for MDR especially in breast cancer cells but no profound data are available on the expression of this potential therapeutic target in clinical breast cancer specimens. We analyzed microarray data of GCS expression in a large cohort of 1,681 breast tumors. Expression of GCS was associated with a positive estrogen receptor (ER) status, lower histological grading, low Ki67 levels and ErbB2 negativity ( P < 0.001 for all). In univariate analysis there was a benefit for disease free survival for patients with tumors displaying low levels of GCS expression but this significance was lost in multivariate Cox regression. Our results suggest ER positive tumors may be the most promising candidates for a potential therapeutic application of GCS inhibitors. [ABSTRACT FROM AUTHOR]

Patients with an early response to neoadjuvant chemotherapy have chemosensitive tumors and a high probability for a pathological complete response at surgery. The relationship between extended chemo- therapy and pathological complete response at surgery was investigated in a clinical trial. Untreated breast cancer patients received two 3-week cycles of docetaxel at 75 mg/rn2, doxorubicin at 50 mg/rn2, and cyclophosphamide at 500 mg/rn2 (TAC). Those whose tumor size decreased by 50% or more by sonographic measurement (ie, reduction in the product of the two largest perpendicular diameters by at least 50%) were classified as responders and randomly assigned to receive four or six more cycles of TAC, for a total of six or eight TAC cycles. The primary aim was to increase the rate of a pathological complete response (defined as no invasive or in situ residual tumor masses in the breast and lymph nodes) from 20% to 26%. Sonographic response rates and rates of breast-conserving surgery and adverse effects were also assessed. All statistical tests were two-sided. Of the 2090 patients in the GeparTrio trial, 1390(66.5%) were randomly assigned as responders after two initial TAC cycles to receive an additional four (n = 704) or six (n = 686) TAC cycles. Rates of pathological complete response were not statistically significantly different between the arms (21.0% with six TAC cycles and 23.5% with eight TAC cycles; difference = 2.5%, 95% confidence interval [Cl] = -1.8% to 6.8%; P= .27). More clinical (48.2% vs 52.9%, difference = 4.7%; 95% Cl = -0.55% to 9.95%; P= .08) and sonographic (22.6% vs 27.6%, difference = 5%; 95% Cl = 0.45% to 9.55%; P= .033) complete responses at surgery were observed with eight TAC cycles than with six TAC cycles. The rate of breast-conserving surgery was similar in both arms (67.5% vs 68.5%, respectively, P= .68). Grade 3 or 4 leukopenia and edema and various grade 1 or 2 adverse events were more frequent in patients receiving eight TAC cycles than in those receiving six cycles. Patients receiving eight TAC cycles had statistically significantly higher sonographic response rates but not pathological complete response rates than those receiving six TAC cycles. However, they also had more toxic effects. So far, eight cycles of TAC cannot be recommended for the whole group of patients responding to two initial cycles of TAC. [ABSTRACT FROM AUTHOR]

The increasing understanding of the pathophysiological background of breast cancer is associated with new molecular techniques, improved risk assessment, targeted therapy and individualized treatment. Gene expression profiling may provide predictive and prognostic gene signatures which could help characterize tumors and enable more tailored therapies. Beyond this, gene expression profiling allows us to better understand tumor development and can help identify new molecular markers which should be investigated in terms of specific clinical objectives. There is also an increasing trend towards translational research in large clinical trials which gives new insight into pathophysiology and the prediction of response according to specific therapeutic approaches. Even if the detection of new molecular markers gives rise to new hypotheses, most studies lack a prospective setting, and thus the use of identified markers or specific gene signatures in clinical routine is still limited. [ABSTRACT FROM AUTHOR]

Background: Expression of polo-like kinase-1 (PLK1), which has several functions in mitotic progression, is elevated in a broad range of human tumors. To investigate the role of PLK1 in neoplastic proliferation, we used the technique of RNA interference.Methods: Cells from several different cancer cell lines (MCF-7 breast cancer cells, HeLa S3 cervical cancer cells, SW-480 colon cancer cells, and A549 lung cancer cells) were transfected with small interfering (si) RNAs targeted against the human PLK1 or lamin genes. Northern and western blot analyses were used to examine PLK1 gene expression in transfected cancer cells and normal cells (human mammary epithelial cells [HMECs]). The phenotype, proliferation, and cell cycle distribution of cells transfected with siRNAs were also monitored by fluorescence microscopy and fluorescence-activated cell sorting analysis.Results: All cancer cell lines transfected with low doses of siRNAs targeted to PLK1 had greatly decreased levels of PLK1 mRNA and protein. siRNA4, which had the strongest inhibitory effect, reduced PLK1 mRNA in MCF-7 cells by 70% and PLK1 protein in MCF-7 cells by 95% 24 hours after transfection. Cell proliferation was reduced by between 66% and 99% 48 hours after transfection, and apoptosis was increased from 1%-5% to 13%-50% in transfected cells. Transfected SW-480 cells were mitotically arrested, and their centrosomes had lost the ability to nucleate microtubules. HMECs took up siRNAs less efficiently than cancer cells, and transfection with siRNAs targeted to PLK1 did not inhibit their proliferation.Conclusions: PLK1 function appears to be essential for centrosome-mediated microtubule events and, consequently, for spindle assembly. siRNAs targeted against human PLK1 may be valuable tools as antiproliferative agents that display activity against a broad spectrum of neoplastic cells at very low doses. [ABSTRACT FROM AUTHOR]

Purpose. In our recent studies, we demonstrated that breast cancer treatment by anti-EGF-R antibody resulted in a significant therapeutic effect in vivo. Furthermore, we were able to elucidate histopathologic parameters with an impact on therapy success. The aim of this study was the evaluation of EGF-R and Her2/neu protein expression on a large series of primary breast cancer, to elucidate if anti-EGF-R antibody therapy is a new therapeutic option for patients who are Her2/neu negative and where, therefore, anti-Her2/neu antibody treatment is not applicable. Methods. We analyzed EGF-R and Her2/neu protein expression of 149 consecutive primary breast cancer specimens by fully quantitative enzyme-linked immunosorbent assay. For evaluation of stochastic independence, we used χ2-test as goodness-of-fit test. Results. We found EGF-R and Her2/neu expression as stochastically independent in primary breast cancer. Conclusions. Anti-EGF-R antibody treatment is a potential therapeutic option for patients with Her2/neu negative breast cancer. [ABSTRACT FROM AUTHOR]

Presents a study that investigated whether growth arrest of tumors treated with anti-epidermal growth factor-receptor (EGF-R) MAb was dependent on EGF-R expression and distinct histopathologic criteria of those neoplasms. Background on EGF; Role of growth factors and their receptors in regulating the growth of malignant cells; Implications of the results.

We previously used DNA array analyses in the molecular profiling of breast cancers. By cluster analysis of 55 patients, we identified a subpopulation of breast cancers--designated class A--that contained a high number of nodal-positive tumours and that had frequently developed distant metastases at the time of diagnosis. We have now analysed follow-up data from these patients. We found that, despite a median of only 23.5 months of follow-up, 11 of 22 patients in class A progressed to metastatic disease, and three of five patients classified as having a nodal status of N0 in this subpopulation developed distant metastases. Our analysis identifies breast-cancer patients with a high risk of disease recurrence, and could act as a first step towards improved patient-adapted therapy. [ABSTRACT FROM AUTHOR]