Purpose
Sphingolipids play important roles in apoptosis and cell proliferation. Sphingosine kinase 1 (SphK1) expression has a prognostic impact in primary breast cancer, but its predictive value is ...currently unknown.
Methods
A total of 112 breast cancer specimens from a prospective neoadjuvant chemotherapy trial (GeparDuo) were studied. Using tissue microarrays of pre-treatment core cut biopsies, we determined the expression of SphK1 by immunohistochemistry. The upper quartile of the cohort according to an immune reactive score of SphK1 was used as cutoff for high expression.
Results
We observed a larger number of samples with high SphK1 expression among ER-negative cancers (36.8 vs. 20.5 % among ER-positive cancers; Fisher test
p
= 0.073). Eighteen of the 112 patients demonstrated a pathological complete response. A significant predictive value for pathological complete response was observed for ER negativity (
p
= 0.003), young age (
p
= 0.037), and high tumor grade (
p
= 0.049). An increased pCR rate was observed in tumors with high SphK1 expression within the luminal subtype (26.7 vs. 5.8 %; Fisher test
p
= 0.040). No significant difference in survival was detected according to SphK1 expression.
Conclusions
Our results suggest that SphK1 may be a predictive factor for pCR after neoadjuvant treatment in luminal type breast cancers and warrants further investigation.
Within 2 decades, neoadjuvant therapy (NAT) has become a standard treatment option in breast cancer. The advantage of NAT is the ability to monitor the treatment effect. Pathological complete ...response (pCR) after NAT is a very good predictor for long-term outcome. Clinical factors, such as age and body mass index, as well as recently identified biomarkers can predict the chance of achieving a pCR. Hormone-receptor status, proliferation markers, immune infiltrates and genetic alterations, such as germline BRCA and PIK3CA, can now be measured almost on a routine basis due to the decreased analysis costs.
Our purpose was to analyze the tissue expression of human epididymis protein-4 (HE4) in borderline tumors of the ovary (BOT) and to correlate it with histological subtypes and clinical features.
...Tumor tissue samples from 25 patients with BOT were stained on tissue microarrays. The percentage of stained tumor cells was represented by grouped immunoreactivity scores (IRS) 0 to 4.
The median patient age was 47 (range=22-73) years. Tumors in most patients (19/25) were staged-FIGO I and presented serous (52%) or mucinous (40%) histology. HE4 immunoreactivity occurred exclusively within the tumor cells. No association between grouped IRS and histological type, age, CA125 and FIGO stage was found. Correlation between HE4 positivity cells and HE4 IRS was significant (p<0.001).
The role of HE4 in BOT remains unclear. Multicenter surveys are needed to more profoundly help in the understanding of the biological and clinical features of BOT.
Abstract Objective The plasminogen activator system (PA) plays an important role in invasion and metastasis of solid tumors. The PA Inhibitor type 1 (PAI-1) is the main physiologic regulator of ...plasminogen activation. A recently characterized protein, PAI-RBP1 (PAI-1 mRNA Binding Protein 1), appears to regulate the stability of PAI-1 mRNA. Expression of PAI-RBP1 (the new, approved gene symbol is SERBP1 ) has not been previously analyzed in human tumors. We present herein for the first time expression analysis of PAI-RBP1 in epithelial ovarian cancer. Methods PAI-RBP1 was identified as gene overexpressed in ovarian cancer by an in silico approach using EST database mining. A thorough expression analysis of PAI-RBP1 and PAI-1 was performed in normal ovary ( n = 4), benign ( n = 6) and malignant ( n = 42) ovarian lesions using non-radioactive RNA in situ hybridization and immunohistochemistry, respectively. Results PAI-RBP1 mRNA and PAI-1 were significantly overexpressed in tumor epithelial cells as compared to benign and normal ovarian tissue. A significant correlation between PAI-RBP1 expression and advanced disease stage (FIGO) was found ( p = 0.042). Conclusion In ovarian cancer, PAI-RBP1 is significantly overexpressed in tumor epithelial cells, suggesting a biological role in tumor invasion and metastasis. Its expression is higher in advanced disease, thus the prognostic significance of PAI-RBP1 in ovarian cancer remains to be evaluated in further studies.
The ubiquitously expressed actin-binding protein, gelsolin, is known to play a role in the modulation of the actin network and in the regulation of cell growth and cell motility. In the present ...study, we analysed the expression of gelsolin in 241 matched cDNA pairs from human normal and tumour tissues using a Cancer Profiling Array. We found a decreased expression of gelsolin in cancer tissue from female reproductive organs, including the ovary. On a protein level, we examined the expression of gelsolin in human ovarian cancer cell lines and in a set of 110 cases of human benign and malignant ovarian tumours. Low levels of gelsolin protein were observed in four of six ovarian carcinoma cell lines, in contrast to its expression in normal ovarian surface epithelial cells. In addition, we found a reduced expression of gelsolin in borderline tumours and ovarian carcinomas compared with the epithelium of normal ovaries and benign adenomas. Decreased gelsolin expression was associated with poorly differentiated carcinomas (
p
=
0.014). No significant association between gelsolin expression and other clinicopathological markers or patient survival could be established. In addition, we investigated the growth regulatory function of gelsolin in human ovarian cancer cell lines using cDNA transfections. Re-expression of gelsolin in OAW42 and ES-2 cells resulted in a suppression of tumour cell survival
in vitro. To explore the mechanism responsible for the downregulation of gelsolin expression in ovarian carcinoma cells, we treated cells with inhibitors of DNA methylation and histone deacetylation. We observed an upregulation of gelsolin in ovarian cancer cells after treatment with both types of inhibitor. Our results suggest that gelsolin might be involved in the growth regulation of human ovarian cancer.
Abstract only
10627
Background: Based on its potential use as a therapeutic target through PARP inhibitors expression of Poly-A-Ribose-Polymerase-1 (PARP-1) has come into scientific focus. ...Furthermore, it could be demonstrated that cytoplasmic PARP-1 expression varies depending on molecular breast cancer subtypes and that it correlates with an increased response to neoadjuvant taxane-anthrazykline containing chemotherapy (von Minckwitz et al., J Clin Oncol 2011). In-vitro-chemotherapy sensitivity and resistance assays (CSRAs) are a means to directly measure chemotherapy sensitivity in a given tumor uninfluenced by host factors. Methods: We conducted a systematic immunohistochemical tissue-microarray (TMA)-based analysis of 550 samples of invasive breast cancers to evaluate the expression of a set of molecular markers including estrogen receptor (ER), progesterone receptor (PR) and HER2 as well as PARP-1. Triple negative breast cancers (TNBC) were identified through lack of (over-)expression of ER, PR and HER2. All carcinomas were analyzed in an in vitro CSRA protocol for epirubicin/docetaxel (ED) and epirubicin/cyclophosphamide (EC). In-vitro-chemotherapy sensitivity was analyzed using an adenosine triphosphate (ATP) bioluminescence assay. Results: Moderate/high expression of PARP-1 was found in 48 and 33% of cases with TNBC and non-TNBC, respectively (p=0.015). No correlation between TNBC phenotype and cytoplasmic expression was observed. However, increased expression of both cytoplasmic and nuclear PARP-1 was correlated with an increased in-vitro sensitivity against ED (p=0.012 and 0.025, respectively) but not EC (p=0.27 and 0.62, respectively). Conclusions: Our results support previous observations demonstrating a significant correlation between expression of PARP-1 and an increased sensitivity against taxane-anthracycline chemotherapy independent of tumor phenotype.
Abstract only
4016
Background: Previous investigations in pancreatic cancer suggested an important prognostic role for SPARC (secreted protein acidic and rich in cysteine) expression in the ...peritumoral stroma but not for cancer-cell cytoplasmic SPARC expression. So far no data from prospective studies in patients after curatively intended surgery are available. Methods: CONKO-001, a prospective randomized phase III study, investigated the role of adjuvant gemcitabine as compared to observation. Tissue samples of 160 patients were collected and analysed by immunohistochemistry for the expression of SPARC in the peritumoral stroma (strong versus not strong =moderate to negative) and in the tumor cell cytoplasm (immunoreactive score IRS 0-12, 0-2 = negative, 3-12 = positive) by a pathologist blinded to clinical outcome. Kaplan-Meier analyses for disease-free survival (DFS) and overall survival (OS) were performed in dependence of SPARC expression. Results: Strong stromal SPARC expression was associated with worse DFS and OS in the overall study population (strong vs not-strong DFS 9.0 vs 12.6 months, p=0.005; OS 19.8 vs 26.6 months (p=0.033). It was highly prognostic in the subgroup treated with gemcitabine (strong vs not-strong DFS 12.1 vs. 18.4 months; p=0.007, OS 17.9 vs 30.2 months, p=0.006), but not in the observation group (strong vs not strong DFS 6.6 vs 7.3 months p=0.767; OS 21.5 vs 18.2 months, p=0.765). Cytoplasmic SPARC expression in the adenocarcinoma cells was also associated with worse patient outcome (positive vs negative DFS 7.4 vs 12.1 months, p=0.041; OS 14.1 vs 25.6 months, p=0.011), again the effect was restricted to patients treated with gemcitabine (positive vs negative DFS 8.3 vs 15.3 months, p=0.002; OS 11.0 vs 28.8 months, p= 0.003; control group DFS 5.8 vs 7.6 months, p=0.844; OS 14.9 vs 20.8 months, p=0.519). Conclusions: Our data confirm the prognostic significance of SPARC expression and demonstrate a significant prognostic factor of SPARC in patients with pancreatic cancer after curatively intended resection. The prognostic impact was restricted to patients who received adjuvant treatment with gemcitabine. In difference to former published data this was found for peritumoral SPARC as well as for SPARC expression in tumor cells.
Human epidermal growth factor receptor 2 ( HER2 , alias ERBB2 )-targeted therapy in breast and gastric cancers depends on the reliable assessment of HER2 protein expression and (in equivocal cases) ...the quantitative evaluation of HER2 gene amplification. Typically, HER2 and centromere 17 gene copy numbers are evaluated using in situ hybridization (ISH) to calculate ratios for which cutoff values dividing nonamplified and amplified cases have been proposed. Although several studies have investigated how laboratory procedures affect diagnostics, a rigorous quantitative assessment of the diagnostic guidelines for data analysis is still missing. Here, we analyze the dependence of the diagnosed HER2 /chromosome 17 ratios on i) sample size (evaluated cells), ii) gene/chromosome signal distributions, and iii) the approach used for quotient calculation using Monte Carlo simulations. Our data show that the current recommendation may lead to statistical HER2 / CHR17 ratio variations of up to 0.94 and may therefore lead to incorrect HER2 status diagnoses, given the ratio threshold of 2.0 defined by the Food and Drug Administration. Moreover, borderline cases may receive different amplification diagnoses, depending on the ratio calculation approach: Brightfield-silver ISH with aggregated signal counts may underestimate the HER2 / CHR17 ratio compared with two-color fluorescence ISH. Our results provide a basis for quantitative rationales behind HER2 diagnostic guidelines that call for increased numbers of evaluated cells and emphasize the importance of well-designed data analysis methods in diagnostic pathology, especially for predictive clinical application.
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