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High levels of γ-glutamyl hydrolase (GGH) are associated with poor prognosis and unfavorable clinical outcomes in invasive breast cancer  [cached]
Shubbar Emman,Helou Khalil,Kovács Anikó,Nemes Szilárd
BMC Cancer , 2013, DOI: 10.1186/1471-2407-13-47
Abstract: Background Previously, we performed analysis of gene expression in 46 axillary lymph node negative tumors and identified molecular gene signatures that resulted in different clinical outcomes. The aim of this study was to determine the correlation of γ-glutamyl hydrolase (GGH), fatty acid amide hydrolase (FAAH), Pirin (PIR) and TAF5-like RNA polymerase II, p300/CBP-associated factor (PCAF)-associated factor, 65 kDa (TAF5L), selected from identified gene signatures, with clinical outcomes as well as classical clinicopathological characteristics in primary invasive breast cancer patients. Methods The protein levels of GGH, FAAH, PIR and TAF5L were assessed by immunohistochemistry (IHC) on a panel of 80 primary invasive breast tumors. Quantitative real-time PCR (qRT-PCR) and western blot analysis were performed to verify the expression levels of the candidate biomarkers. Patient disease-specific survival (DSS) and recurrence-free survival (RFS) were evaluated using the Kaplan-Meier method. The prognostic biomarkers were identified by univariate analysis with a log-rank test and by multivariate analysis with Cox proportional hazards regression models. Results The GGH and FAAH protein levels were significantly up-regulated in invasive breast cancer tumors compared with adjacent non-cancerous tissues. Furthermore, the protein levels of GGH and FAAH were significantly correlated in tumor tissues. Tumoral GGH protein expression was significantly correlated with shorter DSS and RFS. Furthermore, the protein expression of GGH was positively correlated with undifferentiated tumors (BRE grade III) and ER/PR expressing tumors. Multivariate regression analysis showed that only GGH protein expression independently predicts DSS. No such correlations were found for FAAH, PIR and TAF5L protein expression. However, elevated protein levels of FAAH were positively associated with high number of lymph node involvement and upregulated levels of PIR were positively related with lymph node metastasis. The TAF5L was pronouncedly down-regulated in primary invasive breast cancer tissues compared to matched adjacent non-cancerous tissues. Conclusion These data show for the first time that cytoplasmic GGH might play a relevant role in the development and progression of invasive breast cancer, warranting further investigations. Our findings suggest that GGH serve as a potential biomarker of unfavorable clinical outcomes over short-term follow-up in breast cancer. The GGH may be a very attractive targeted therapy for selected patients.
Prognostic Breast Cancer Signature Identified from 3D Culture Model Accurately Predicts Clinical Outcome across Independent Datasets  [PDF]
Katherine J. Martin, Denis R. Patrick, Mina J. Bissell, Marcia V. Fournier
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0002994
Abstract: Background One of the major tenets in breast cancer research is that early detection is vital for patient survival by increasing treatment options. To that end, we have previously used a novel unsupervised approach to identify a set of genes whose expression predicts prognosis of breast cancer patients. The predictive genes were selected in a well-defined three dimensional (3D) cell culture model of non-malignant human mammary epithelial cell morphogenesis as down-regulated during breast epithelial cell acinar formation and cell cycle arrest. Here we examine the ability of this gene signature (3D-signature) to predict prognosis in three independent breast cancer microarray datasets having 295, 286, and 118 samples, respectively. Methods and Findings Our results show that the 3D-signature accurately predicts prognosis in three unrelated patient datasets. At 10 years, the probability of positive outcome was 52, 51, and 47 percent in the group with a poor-prognosis signature and 91, 75, and 71 percent in the group with a good-prognosis signature for the three datasets, respectively (Kaplan-Meier survival analysis, p<0.05). Hazard ratios for poor outcome were 5.5 (95% CI 3.0 to 12.2, p<0.0001), 2.4 (95% CI 1.6 to 3.6, p<0.0001) and 1.9 (95% CI 1.1 to 3.2, p = 0.016) and remained significant for the two larger datasets when corrected for estrogen receptor (ER) status. Hence the 3D-signature accurately predicts breast cancer outcome in both ER-positive and ER-negative tumors, though individual genes differed in their prognostic ability in the two subtypes. Genes that were prognostic in ER+ patients are AURKA, CEP55, RRM2, EPHA2, FGFBP1, and VRK1, while genes prognostic in ER? patients include ACTB, FOXM1 and SERPINE2 (Kaplan-Meier p<0.05). Multivariable Cox regression analysis in the largest dataset showed that the 3D-signature was a strong independent factor in predicting breast cancer outcome. Conclusions The 3D-signature accurately predicts breast cancer outcome across multiple datasets and holds prognostic value for both ER-positive and ER-negative breast cancer. The signature was selected using a novel biological approach and hence holds promise to represent the key biological processes of breast cancer.
Endothelin-1 Enriched Tumor Phenotype Predicts Breast Cancer Recurrence  [PDF]
Deimante Tamkus,Alla Sikorskii,Kathleen A. Gallo,David A. Wiese,Cheryl Leece,Burra V. Madhukar,Simona C. Chivu,Shalini Chitneni,Nikolay V. Dimitrov
ISRN Oncology , 2013, DOI: 10.1155/2013/385398
Abstract: Introduction. Breast cancer recurrence can develop years after primary treatment. Crosstalk between breast cancer cells and their stromal microenvironment may influence tumor progression. Our primary study aim was to determine whether endothelin-1 (ET-1) expression in tumor and stroma predicts breast cancer relapse. The secondary aim was to determine ET-1/endothelin receptor A (ETAR) role on signaling pathways and apoptosis in breast cancer. Experimental Design. Patients with histologically documented stages I–III invasive breast cancer were included in the study. ET-1 expression by immunohistochemistry (IHC) in tumor cells and stroma was analyzed. Association between ET-1 expression and clinical outcome was assessed using multivariate Cox proportional hazard model. Kaplan-Meier curves were used to estimate disease-free survival (DFS). In addition, the effect of ET-1/ETAR on signaling pathways and apoptosis was evaluated in MCF-7 and MDA-MB-231 breast cancer cells. Results. With a median followup of 7 years, ET-1 non-enriched tumor phenotype had a significant association with favorable disease-free survival ( ; 95% CI 0.03–0.77; value <0.02). ER negativity, advanced stage of disease and ET-1-enriched tumor phenotype were all associated with a higher risk for recurrence. Experimental study demonstrated that ET-1 stimulation promoted Akt activation in MCF-7 and MDA-MB-231 cells. Furthermore, silencing of ETAR induced apoptosis in both hormone receptor negative and hormone receptor positive breast cancer cells. Conclusions. We found ET-1 expression in tumor and stroma to be an independent prognostic marker for breast cancer recurrence. Prospective studies are warranted to examine whether ET-1 expression in tumor/stroma could assist in stratifying patients with hormone receptor positive breast cancer for adjuvant therapy. 1. Introduction Breast cancer metastases can develop years after primary tumor treatment [1]. Current adjuvant systemic or regional therapies eliminate a majority of cancer cells. However, a subset of cancer cells, which are not effectively eradicated by the treatment, may maintain their potential for further growth. Tumor cells may interact with their stromal microenvironment to either facilitate or delay tumor dissemination, thus influencing tumor recurrence in breast cancer patients [2]. Thirty to 40% of patients with early-stage breast cancer at the time of diagnosis have disseminated tumor cells detected in the bone marrow [3]. The majority of these disseminated tumor cells die, but some of them remain dormant and have the capacity to
The Clinicopathologic Characteristics and Prognostic Significance of Triple - Negative Invasive Breast Cancer Phenotype
Jelena Maksimenko, Inta Liepniece-Karele, Arvids Irmejs, Genadijs Trofimovics
Acta Chirurgica Latviensis , 2011, DOI: 10.2478/v10163-012-0003-y
Abstract: Introduction. Triple-negative phenotype is defined by a primary tumor that is estrogen, progesterone and HER2/neu receptor negative. This cancer subtype is important because of its close relation to the basal-like breast cancer and its profound investigation could help to develop novel therapeutic strategies. Aim of the study. Is to evaluate triple-negative breast cancer(TNBC) clinicopathological characteristics and prognostic significance. Materials and Methods. We have retrospectively analyzed 76 unselected invasive breast cancer patients' cases diagnosed between 2005 and 2010 from RAKUS Pathological center and PSKUS. TNBC were defined as tumors that were estrogen, progesterone receptor negative, and HER2/neu negative. The clinicopathological features and prognostic significance were explored. Results. 45 of 76 cases (59.2%) were defined as TNBC. The median follow-up from the original diagnosis until analysis was 24(range, 5- 48) months in the TNBC group and 22.6 (range, 3- 65) months in the non- TNBC group. The mean age at diagnosis was significantly younger for the TNBC group compared with non-TNBC group (55.5 versus 62.1years, respectively; p < 0.021). There was no statistically significant difference between the two groups in the T stage, lymph node status and histological type and stage of disease. Patients in the TNBC group were more likely to have grade III tumors (58.8% versus 29.2%; p< 0.05). In the TNBC group in 2 (4.4%) patients' cases local recurrence occurred, versus 0 (0.0%) in the other group within the follow-up period (p< 0.051). The average time to local recurrence for patients with TNBC was 14 months (range, 12 - 16 months). A high proportion of patients with TNBC experienced distant recurrence compared with patients with non- TNBC (22.2% versus 0.0%, respectively; p< 0.017). The average time to distant recurrence for patients with TNBC was 14.2 months (range, 5 - 32 months). In the TNBC group 7 (15.5%) breast cancer-related deaths were detected versus no deaths in the other group, respectively. Conclusion. TNBC was associated with younger age and higher histologic grade. TNBC had aggressive clinical course and high rate of early recurrence.
Histone demethylase GASC1 - a potential prognostic and predictive marker in invasive breast cancer  [cached]
Berdel Bozena,Nieminen Kaisa,Soini Ylermi,Tengstr?m Maria
BMC Cancer , 2012, DOI: 10.1186/1471-2407-12-516
Abstract: Background The histone demethylase GASC1 (JMJD2C) is an epigenetic factor suspected of involvement in development of different cancers, including breast cancer. It is thought to be overexpressed in the more aggressive breast cancer types based on mRNA expression studies on cell lines and meta analysis of human breast cancer sets. This study aimed to evaluate the prognostic and predictive value of GASC1 for women with invasive breast cancer. Methods All the 355 cases were selected from a cohort enrolled in the Kuopio Breast Cancer Project between April 1990 and December 1995. The expression of GASC1 was studied by immunohistochemistry (IHC) on tissue microarrays. Additionally relative GASC1 mRNA expression was measured from available 57 cases. Results In our material, 56% of the cases were GASC1 negative and 44% positive in IHC staining. Women with GASC1 negative tumors had two years shorter breast cancer specific survival and time to relapse than the women with GASC1 positive tumors (p=0.017 and p=0.034 respectively). The majority of GASC1 negative tumors were ductal cases (72%) of higher histological grade (84% of grade II and III altogether). When we evaluated estrogen receptor negative and progesterone receptor negative cases separately, there was 2 times more GASC1 negative than GASC1 positive tumors in each group (chi2, p= 0.033 and 0.001 respectively). In the HER2 positive cases, there was 3 times more GASC1 negative cases than GASC1 positives (chi2, p= 0.029). Patients treated with radiotherapy (n=206) and hormonal treatment (n=62) had better breast cancer specific survival, when they were GASC1 positive (Cox regression: HR=0.49, p=0.007 and HR=0.33, p=0.015, respectively). The expression of GASC1 mRNA was in agreement with the protein analysis. Conclusions This study indicates that the GASC1 is both a prognostic and a predictive factor for women with invasive breast cancer. GASC1 negativity is associated with tumors of more aggressive histopathological types (ductal type, grade II and III, ER negative, PR negative). Patients with GASC1 positive tumors have better breast cancer specific survival and respond better to radiotherapy and hormonal treatment.
Relationship between Tumor Heterogeneity Measured on FDG-PET/CT and Pathological Prognostic Factors in Invasive Breast Cancer  [PDF]
Michael Soussan, Fanny Orlhac, Marouane Boubaya, Laurent Zelek, Marianne Ziol, Véronique Eder, Irène Buvat
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0094017
Abstract: Background There is currently little support to understand which pathological factors led to differences in tumor texture as measured from FDG PET/CT images. We studied whether tumor heterogeneity measured using texture analysis in FDG-PET/CT images is correlated with pathological prognostic factors in invasive breast cancer. Methods Fifty-four patients with locally advanced breast cancer who had an initial FDG-PET/CT were retrospectively included. In addition to SUVmax, three robust textural indices extracted from 3D matrices: High-Gray-level Run Emphasis (HGRE), Entropy and Homogeneity were studied. Univariate and multivariate logistic regression was used to identify PET parameters associated with poor prognosis pathological factors: hormone receptor negativity, presence of HER-2 and triple negative phenotype. Receiver operating characteristic (ROC) curves and the (AUC) analysis, and reclassification measures, were performed in order to evaluate the performance of combining texture analysis and SUVmax for characterizing breast tumors. Results Tumor heterogeneity, measured with HGRE, was higher in negative estrogen receptor (p = 0.039) and negative progesterone receptor tumors (p = 0.036), and in Scarff-Bloom-Richardson grade 3 tumors (p = 0.047). None of the PET indices could identify HER-2 positive tumors. Only SUVmax was positively correlated with Ki-67 (p<0.0004). Triple negative breast cancer (TNBC) exhibited higher SUVmax (Odd Ratio = 1.22, 95%CI [1.06–1.39],p = 0.004), lower Homogeneity (OR = 3.57[0.98–12.5],p = 0.05) and higher HGRE (OR = 8.06[1.88–34.51],p = 0.005) than non-TNBC. Multivariate analysis showed that HGRE remained associated with TNBC (OR = 5.27[1.12–1.38],p = 0.03) after adjustment for SUVmax. Combining SUVmax and HGRE yielded in higher area under the ROC curves (AUC) than SUVmax for identifying TNBC: AUC = 0.83 and 0.77, respectively. Probability of correct classification also increased in 77% (10/13) of TNBC and 71% (29/41) of non-TNBC (p = 0.003), when combining SUVmax and HGRE. Conclusions Tumor heterogeneity measured on FDG-PET/CT was higher in invasive breast cancer with poor prognosis pathological factors. Texture analysis might be used, in addition to SUVmax, as a new tool to assess invasive breast cancer aggressiveness.
Potential prognostic value of heat-shock protein 90 in the presence of phosphatidylinositol-3-kinase overexpression or loss of PTEN, in invasive breast cancers
Chang Song, So Park, Keun-Yong Eom, Jee Kim, Sung-Won Kim, Jae Kim, In Kim
Breast Cancer Research , 2010, DOI: 10.1186/bcr2557
Abstract: Immunohistochemical analyses of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), PI3K-p110α, phospho-AKT, phospho-p70S6 kinase, phospho-S6 ribosomal protein, phospho-RAF, phospho-p44/42 MAPK, and heat-shock protein 90 (HSP90) were performed on tumor samples from 212 patients with invasive breast cancer. Statistically significant relations between protein expression, clinicopathologic factors, and relapse-free survival (RFS) were analyzed.Expression of HSP90 was associated with 5-year RFS, as well as T stage, N stage, histologic grade, estrogen receptor (ER) expression, human epidermal growth factor receptor 2 (HER2) expression, and the Ki-67 proliferation index. On multivariate analysis, coexpression of HSP90 and PI3K-p110α or expression of HSP90 along with PTEN loss demonstrated significantly worse RFS. In subgroup analyses, both exhibited strong prognostic significance in HER2-positive cases, but not in HER2-negative cases.The coexpression of HSP90 with PI3K-p110α or expression of HSP90 along with PTEN loss has a potential as a molecular prognostic marker to predict early relapse in patients with invasive breast cancers.Disruption of critical cell-signaling pathways responsible for cell growth and survival has been shown to contribute to atypical cell proliferation, to metastatic competence of breast cancer cells, and may be responsible for therapeutic resistance of some breast cancers. In the field of targeted breast cancer therapy, several prognostic markers including clinical stage [1], histologic grade [2], estrogen receptor (ER)/progesterone receptor (PR) status [3-5], human epidermal growth factor receptor-2 (HER2) [6,7], and the Ki-67 proliferation index [8] have already been identified and validated. Additional molecular markers that have potential prognostic significance also have been identified.HER2 is a cell-surface receptor tyrosine kinase (RTK), which is amplified in one fourth of breast cancers and confers a more aggressive clinical
Relationship between the expression of cyclooxygenase 2 and MDR1/P-glycoprotein in invasive breast cancers and their prognostic significance
Pawel Surowiak, Verena Materna, Rafal Matkowski, Katarzyna Szczuraszek, Jan Kornafel, Andrzej Wojnar, Marek Pudelko, Manfred Dietel, Carsten Denkert, Maciej Zabel, Hermann Lage
Breast Cancer Research , 2005, DOI: 10.1186/bcr1313
Abstract: Immunohistochemical reactions were performed using monoclonal antibodies against COX-2 and MDR1/P-gp on samples originating from 104 cases of primary invasive breast cancer.COX-2-positive cases were shown to demonstrate higher expression of MDR1/P-gp (P < 0.0001). The studies also demonstrate that COX-2 expression was typical for cases of a higher grade (P = 0.01), a shorter overall survival time (P < 0.0001) and a shorter progression-free time (P < 0.0001). In the case of MDR1/P-gp, its higher expression characterised cases of a higher grade (P < 0001), with lymph node involvement (P < 0001), and shorter overall survival (P < 0.0001) and progression-free time (P < 0.0001).Our studies confirmed the unfavourable prognostic significance of COX-2 and MDR1/P-gp. We also document a relationship between COX-2 and MDR1/P-gp, which suggests that COX-2 inhibitors should be investigated in trials as a treatment supplementary to chemotherapy of breast cancers.Breast cancer is the most common malignant tumour of females in the western world [1]. The incidence of breast cancer remains high, and its clinical courses are highly variable. It is of general importance to predict the biology of the tumour and, thus, the course of the disease in the individual patient to ensure adequate therapy and patient surveillance [2]. The principal therapeutic approach in breast cancer involves surgery. In advanced cases supplementary therapy is needed, involving pharmacotherapy and/or radiotherapy. Among the pharmacological means, tamoxifen used to be applied most frequently, as well as various chemotherapeutic regimes, including CMF (cyclophosphamide, methothrexate and 5-fluorouracil), anthracyclines and paclitaxel [3,4]. The main reason for therapeutic failure in cases of invasive breast cancers involves resistance to anti-estrogenic treatment and to chemotherapy [5,6]. Identification of the factors that characterise the resistant cases would permit immediate treatment of the patients with alt
A Prognostic Gene Expression Profile That Predicts Circulating Tumor Cell Presence in Breast Cancer Patients  [PDF]
Timothy J. Molloy, Paul Roepman, Bj?rn Naume, Laura J. van't Veer
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0032426
Abstract: The detection of circulating tumor cells (CTCs) in the peripheral blood and microarray gene expression profiling of the primary tumor are two promising new technologies able to provide valuable prognostic data for patients with breast cancer. Meta-analyses of several established prognostic breast cancer gene expression profiles in large patient cohorts have demonstrated that despite sharing few genes, their delineation of patients into “good prognosis” or “poor prognosis” are frequently very highly correlated, and combining prognostic profiles does not increase prognostic power. In the current study, we aimed to develop a novel profile which provided independent prognostic data by building a signature predictive of CTC status rather than outcome. Microarray gene expression data from an initial training cohort of 72 breast cancer patients for which CTC status had been determined in a previous study using a multimarker QPCR-based assay was used to develop a CTC-predictive profile. The generated profile was validated in two independent datasets of 49 and 123 patients and confirmed to be both predictive of CTC status, and independently prognostic. Importantly, the “CTC profile” also provided prognostic information independent of the well-established and powerful ‘70-gene’ prognostic breast cancer signature. This profile therefore has the potential to not only add prognostic information to currently-available microarray tests but in some circumstances even replace blood-based prognostic CTC tests at time of diagnosis for those patients already undergoing testing by multigene assays.
The expression level of HJURP has an independent prognostic impact and predicts the sensitivity to radiotherapy in breast cancer
Zhi Hu, Ge Huang, Anguraj Sadanandam, Shenda Gu, Marc E Lenburg, Melody Pai, Nora Bayani, Eleanor A Blakely, Joe W Gray, Jian-Hua Mao
Breast Cancer Research , 2010, DOI: 10.1186/bcr2487
Abstract: We measured HJURP expression level in human breast cancer cell lines and primary breast cancers by Western blot and/or by Affymetrix Microarray; and determined its associations with clinical variables using standard statistical methods. Validation was performed with the use of published microarray data. We assessed cell growth and apoptosis of breast cancer cells after radiation using high-content image analysis.HJURP was expressed at higher level in breast cancer than in normal breast tissue. HJURP mRNA levels were significantly associated with estrogen receptor (ER), progesterone receptor (PR), Scarff-Bloom-Richardson (SBR) grade, age and Ki67 proliferation indices, but not with pathologic stage, ERBB2, tumor size, or lymph node status. Higher HJURP mRNA levels significantly decreased disease-free and overall survival. HJURP mRNA levels predicted the prognosis better than Ki67 proliferation indices. In a multivariate Cox proportional-hazard regression, including clinical variables as covariates, HJURP mRNA levels remained an independent prognostic factor for disease-free and overall survival. In addition HJURP mRNA levels were an independent prognostic factor over molecular subtypes (normal like, luminal, Erbb2 and basal). Poor clinical outcomes among patients with high HJURP expression were validated in five additional breast cancer cohorts. Furthermore, the patients with high HJURP levels were much more sensitive to radiotherapy. In vitro studies in breast cancer cell lines showed that cells with high HJURP levels were more sensitive to radiation treatment and had a higher rate of apoptosis than those with low levels. Knock down of HJURP in human breast cancer cells using shRNA reduced the sensitivity to radiation treatment. HJURP mRNA levels were significantly correlated with CENPA mRNA levels.HJURP mRNA level is a prognostic factor for disease-free and overall survival in patients with breast cancer and is a predictive biomarker for sensitivity to radiotherapy
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