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Background In breast cancer, the role of epigenetic alterations including modifications of the acetylation status of histones in carcinogenesis has been an important research focus during the last years. An increased deacetylation of histones leads to increased cell proliferation, cell migration, angiogenesis and invasion. Class 1 histone deacetylases (HDAC) seem to be most important during carcinogenesis. Methods The immunhistochemical expression of HDAC1, 2 and 3 was analyzed on tissue microarrays (TMAs) from 238 patients with primary breast cancer. We analyzed the nuclear staining intensity (negative, weak, moderate, strong) as well as the percentage of positive tumor cells and calculated the immunoreactivity score (0–12). Expression was correlated with clinicopathological parameters and patient survival. Results In this cohort, we found a differential positive expression of HDAC1, HDAC2 and HDAC3. HDAC2 and HDAC3 expression was significantly higher in less differentiated tumors: HDAC2 (n=207), p<0.001 and HDAC3 (n=220), p<0.001 and correlated with negative hormone receptor status: HDAC2 (n=206), p=0.02 and HDAC3 (n=219), p=0.04. Additionally, a high HDAC2 expression was significantly associated with an overexpression of HER2 (n=203, p=0.005) and the presence of nodal metastasis (n=200, p=0.04). HDAC1 was highly expressed in hormone receptor positive tumors (n=203; p<0.001). Conclusion As a conclusion, our results show that the class-1 HDAC isoenzymes 1, 2 and 3 are differentially expressed in breast cancer. HDAC2 and HDAC3 are strongly expressed in subgroups of tumor with features of a more aggressive tumor type.

Beside their structural role for the cell membrane the family of sphingolipids act as effector molecules in signal transduction with links to various aspects of cancer initiation, progression and treatment response. The “sphingolipid rheostat” balances between apoptosis inducing ceramid and growth promoting sphingosine-1-phosphate. We analyzed gene expression of 43 proteins from this pathway in different subtypes of breast cancer using microarray data of 1,269 tumor samples (test set n  = 171; validation sets n  = 1098) and observed significant differences for several genes. Sphingosine kinase 1 (SPHK1), ceramide galactosyltransferase (UGT8), and Ganglioside GD3-Synthase (ST8SIA1) displayed higher expression among ER negative tumors. In contrast, glucosylceramidsynthase (GCS), dihydroceramidsynthases (LASS4, LASS 6) and acid ceramidase (ASAH1) were higher expressed in ER positive samples. Survival analysis revealed a worse outcome of patients with high SPHK1 expression. To avoid a confounding effect of the ER status we also restricted the analysis to 750 patients with ER positive tumors. Again a worse outcome was observed for tumors displaying high SPHK1 expression. While 75.8 ± 1.9% of the patients with tumors low in SPHK1 expression were free of metastasis at 5 years, this was the case for only 64.9 ± 3.6% of patients with tumors displaying high SPHK1 expression ( P  = 0.008). Immunohistochemistry identified the carcinoma cells as the major source of SPHK1 expression in the tumor. The correlation of SPHK1 with a poor prognosis as well as its high expression among ER negative tumors are in line with the antiapoptotic and proliferative properties of its product sphingosine-1-phosphate. Targeting of the sphingolipid rheostat may thus open new treatment options.

Studies have shown that ALDH1A1 expression in the breast is associated with worse clinical outcome. ALDH1A1 inactivates cyclophosphamide, which is an integral agent in breast cancer chemotherapy regimens. The purposes of this study were to verify these results, to correlate ALDH1A1 expression with clinical outcome in patients treated with cyclophosphamide as part of the chemotherapy (adjuvant or neoadjuvant), and to evaluate ALDH1A1 as a useful marker to predict the clinical outcome of breast cancer subsets. A total of 513 primary breast cancers were studied. Tissue microarrays of the studied cases were stained with ALDH1A1. Key clinicopathological information was obtained. Disease-free survival and overall survival were calculated. Patients with neoadjuvant therapy who had substantial residual cancer burden (RCB) were included in the study. Fisher's exact test and Kaplan–Meier methods were used for statistical analysis. ALDH1A1 was expressed in 53 (10%) patients, with a higher frequency in triple negative, followed by HER2+, and finally hormonal receptor+/HER2− ( P <0.0001). Tumors with advanced stage, node-positive, or larger tumor size were correlated with ALDH1A1 expression ( P =0.006, P <0.0001, and P =0.05, respectively). ALDH1A1 expression was also correlated with worse disease-free survival ( P <0.006) and overall survival ( P <0.01) in patients who were treated with neoadjuvant chemotherapy. In all, 8 of 22 (36%) received neoadjuvant chemotherapy and died of disease-expressed ALDH1A1 ( P =0.008). Similarly, 8 of 23 (35%) who received neoadjuvant chemotherapy and had tumor recurrence expressed this marker ( P =0.002). The risk of recurrence was fivefold greater than negative ALDH1A1 tumors. The risk of recurrence became 11-fold greater when cyclophosphamide but not trastuzumab was part of the regimen. Our results are consistent with previous studies. Moreover, we found that ALDH1A1 could be a useful marker to predict worse clinical outcome after chemotherapy in the neoadjuvant setting with substantial RCB. However, a larger cohort is required to verify our results.

Purpose The aim of this study is to evaluate the prognostic value of the Mitotic Activity Index (MAI) in combination with the human epidermal growth factor receptor (Her2) for distant metastases-free survival (DMFS) and disease-specific survival (DSS) in breast cancer and compare it with the immunohistochemically (IHC) profile types. Methods Analyses were based on 2.923 breast-conserving breast cancer specimens with known MAI, Her2 status, and hormone receptor status, resulting in 2.678 Her2MAI combinations, MAI ≤ 12/Her2negative, MAI > 12/Her2negative, MAI > 12/Her2positive, and MAI ≤ 12/Her2positive, and 2.560 IHC profile types, luminal A, luminal B, triple negative, and non-luminal Her2positive. Results For DMFS, the MAI > 12/Her2negative combination showed a significantly worse outcome in multivariate analyses compared to the MAI ≤ 12/Her2negative combination. None of the IHC profile types showed significantly different outcomes for DMFS and DSS as compared to luminal A. We performed a separate analysis on age and lymph node status. The significance of MAI > 12/Her2negative seems to be limited to women ≤ 55 years for both DMFS and DSS. However, with respect to DSS, this seems to be limited to node negative cases. The IHC profile types for DSS, luminal B showed a significantly worse outcome for women > 55 years compared to that for luminal A, although it showed rather wide confidence interval. Conclusion The MAI > 12/Her2negative combination seems to be a strong prognosticator for DMFS and DSS, particularly for women ≤ 55 years. However, none of the IHC profile types seems to be a prognosticator in breast cancer.

Background A number of studies have indicated that patients obtaining a pathological complete response (pCR) from neoadjuvant chemotherapy (NAC) have a good prognosis; however, prognostic factors for non-pCR patients are not yet well-established. By examining remnant cancer in non-pCR patients, the expression of cleaved Caspase 3 (Casp3), an activated apoptotic marker, was immunohistochemically investigated to determine whether this protein has the potential to serve as a novel marker for predicting patient outcomes. Methods We investigated 218 patients with invasive breast cancer who received NAC and underwent surgery during the 2006 through 2008 period at our institution. Following surgery, standard adjuvant endocrine therapy was administered if a tumor was hormone receptor-positive. Casp3 was evaluated in remnant cancer based on the number of positive cells in five high-power fields. Results pCR was obtained in 49 patients, and 50 of the 169 non-pCR patients developed recurrences during the median 82-month observation period. We found large tumor size, lymph node involvement, lymph vessel invasion, estrogen receptor-negative, progesterone receptor-negative, high Ki67 and high Casp3 expression to be factors related to tumor recurrence. A logistic regression model revealed that lymph node involvement, as well as high Ki67 and Casp3, to be factors independently predicting recurrence, while lymph vessel invasion and high Ki67 expression were found to be related to breast cancer mortality. Conclusions Patients with remnant cancer showing high Casp3 expression had poor outcomes. Our results showed that Casp3 is a potential prognostic marker for non-pCR patients.

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.

Purpose Receptor-like protein tyrosine phosphatase kappa (PTPRK) has been shown to exhibit homophilic binding. It is a putative tumour suppressor in primary central nervous system lymphomas and colorectal cancer. The present study investigated the expression of PTPRK in breast cancer and the biological impact of PTPRK on breast cancer cells. Methods Expression of PTPRK protein and gene transcript was examined in a cohort of breast cancer patients. The association of PTPRK transcript level and pathological and clinical aspects was then analysed. Knockdown of PTPRK in breast cancer cells was performed using a specific anti-PTPRK transgene. The impact of PTPRK knockdown on breast cancer cells was investigated using in vitro cell function assays. Results Lower levels of PTPRK transcripts were seen in the advanced breast cancer. The reduced PTPRK transcript levels were associated with poor prognosis of the disease. PTPRK transcript levels were decreased in the primary tumours of patients who died from breast cancer or had metastases. Patients with lower expression of PTPRK had shorter survival compared with those higher expression levels of PTPRK. Knockdown of PTPRK resulted in increased proliferation, adhesion, invasion, and migration of breast cancer cells in vitro. Conclusions Decreased expression of PTPRK in breast cancer is correlated with poor prognosis. PTPRK is a negative regulator of adhesion, invasion, migration, and proliferation of breast cancer cells. This suggests that PTPRK is a potential tumour suppressor in breast cancer.

Aim: The aims of this study are to evaluate the serum levels of paraoxonase (PON) and arylesterase (ARE) in breast cancer (BC) patients; to determine their relationship with chemotherapy requirements in BC; and to find a cut-off value to assess subjects with a higher risk of BC. Subjects and Methods: A total of 40 BC patients and 33 age-matched healthy women were included in this study. Beside other biochemical parameters, participants' serum PON and ARE levels were determined and analyzed. Results: Serum PON and ARE levels were found decreased in sera of the patients (96.44 ± 21 and 159.75 ± 15.75 U/L, respectively)compared to controls (158.39 ± 23.04 and 239.33 ± 32.98 U/L, respectively) (P = 0.001 for both). Subgroup analysis of the BC patients revealed that both serum PON and ARE levels were lower in patients who needed neoadjuvant chemotherapy (NAC), compared to those who did not (P = 0.024 and 0.02, respectively). We determined a cut-off value of PON according to the receiver operating characteristic curve analysis as 131.2 U/L (sensitivity 97.5% and specificity 93.9%). Conclusion: BC patients have lower serum PON and ARE levels than healthy controls. Also, serum ARE levels (but not PON) were negatively correlated with body mass index in BC patients. Both serum PON and ARE levels were lower in patients who needed NAC than in patients who did not need such therapy.

TOP2A gene encodes topoisomerase II alpha, the direct molecular target of anthracyclines. This gene is frequently coamplified with HER2. The aims of this study were to analyse the pattern of TOP2A amplification and protein expression in relation to the molecular subgroups of breast cancers; and to define the impact of TOP2A amplification on the outcome of a series of patients homogeneously treated with adjuvant anthracyclines. A cohort of 245 patients with early breast cancer homogeneously treated with anthracyclines in the adjuvant setting was selected. A tissue microarray containing these cancers was used to determine HER2 and TOP2A gene copy number by means of chromogenic in situ hybridization. Immunohistochemical staining of topoisomerase II alpha was also performed using a monoclonal antibody (Ki-S1). TOP2A amplification and protein expression were correlated with classical prognostic parameters, expression of immunohistochemical markers and with a gene expression profiling classification using surrogate immunohistochemical markers. Kaplan-Meier method was used to construct survival curves and results were compared with log-rank test. TOP2A amplification was restricted to tumours with HER2 amplification and was significantly associated with ER positivity. In the subgroup of patients with HER2 amplified tumours, TOP2A amplification predicted a better overall survival and disease free survival (P = 0.028 and 0.026, respectively). On multivariate analysis, TOP2A amplification maintained its predictive value for DFS. TOP2A amplification is likely to be a useful marker to predict the subset of patients who will benefit from anthracyclines.

Matrix metalloproteinases play a crucial role in the cancer invasion and metastasis, angiogenesis and tumorigenicity. A single guanine insertion--the 1G/2G polymorphism in the promoter of the matrix metalloproteinase 1 (MMP-1) gene creates a binding site for the transcription factor AP-1 and thus may affect the transcription level of MMP-1. The C-->T substitution at the polymorphic site of the MMP-9 gene promoter results in a higher transcription activity of the T-allelic promoter trough the loss of binding site for a repressor protein. The aim of this work was to investigate the influence of 1G/2G and C-->T polymorphisms on the MMP-1 and MMP-9 level and therefore on the occurrence and progression of breast cancer. We investigated the distribution of genotypes and frequency of alleles of the 1G/2G and C-->T polymorphisms for 270 patients with breast cancer and 300 healthy women served as control. The genotypes were determined by RFLP-PCR. Additionally, we estimated the level of MMP-1 and MMP-9 antigens in tumor samples and normal breast tissue using ELISA. The levels of MMP-1 in tumor samples of node positive patients ware significantly higher than in samples of node negative patients (p<0.05). Increased level of MMP-9 correlates with Bloom-Richardson grading III (p<0.05), increased tumor size (p<0.05) and absence of estrogen and progesterone receptors (p<0.01). Additionally, both MMP-1 and MMP-9 levels were higher in tumor than in the normal breast tissue. We showed the higher risk of metastasis development in lymph node for the 2G/2G genotype (OR=2.14; CI 95% 1.24;3.69) and the 2G allele carriers (OR=1.68; CI 95% 1.19;2.39). We found correlation between the T allele (OR=2.61; CI 95% 1.33;4.87), 2G (OR=2.58; CI 95% 1.35;4.91) and malignance. The results suggest that MMP-1 is responsible for the local invasion and MMP-9 is associated with the malignance and the growth of the tumor. We suggest that the 2G allele of the 1G/2G MMP-1 gene polymorphism may be associated with the lymph node metastasis in patients with breast cancer and therefore it can be considered as a progression marker in this disease.