67 research outputs found
Bestimmung der Proliferation: Stanze oder Resektat?: Diskrepanzen bei niedrig und stark proliferierenden Mammakarzinomen
Zusammenfassung: Hintergrund: Die Bestimmung der Proliferationsfraktion beim invasiven Mammakarzinom wird immer wichtiger und eine klare Standardisierung ist noch ausstehend. Je nach Institut wird die Proliferationsfraktion an der Stanzbiopsie (SB) oder am Operationspräparat (OP) bestimmt. Material und Methode: Wir untersuchten die Interobservervariabilität und die Resultate von SB und entsprechendem OP. Zwei Pathologen evaluierten unabhängig voneinander die mittels Ki-67 bestimmte Proliferationsfraktion an 90Mammakarzinomen. Die Resultate wurden quantifiziert, kategorisiert und miteinander verglichen. Ergebnisse: Identische Resultate (Schätzung in 5%-Stufen) wurden in 43% der Fälle (n = 39) SB, 47% (n =42) OP und in 60% (n = 54) zwischen SB und OP erhoben. Die Bildung von Proliferationskategorien (niedrig:≤ 15%; mittel:20-30%; hoch: ≥ 35%) ergab folgende Resultate: 76% (n =68) SB, 82% (n = 74) OP und 81% (n = 73) zwischen SB und OP. Schlussfolgerung: Die Interobservervariabilität ist deutlich (SB: kappa = 0,32; OP: kappa =0,34), wird aber durch Bildung von Proliferationskategorien markant verbessert (SB: kappa =0,62; OP: kappa = 0,72; 60% auf 81%). Eine Neubestimmung bei niedriger Proliferationsfraktion an der SB ist zu erwägen, da diese in 12% der Fälle am OP höher liegen kan
ERMP1, a novel potential oncogene involved in UPR and oxidative stress defense, is highly expressed in human cancer
Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) are highly activated in cancer and involved in tumorigenesis and resistance to anti-cancer therapy. UPR is becoming a promising target of anti-cancer therapies. Thus, the identification of UPR components that are highly expressed in cancer could offer new therapeutic opportunity. In this study, we demonstrate that Endoplasmic Reticulum Metallo Protease 1 (ERMP1) is broadly expressed in a high percentage of breast, colo-rectal, lung, and ovary cancers, regardless of their stage and grade. Moreover, we show that loss of ERMP1 expression significantly hampers proliferation, migration and invasiveness of cancer cells. Furthermore, we show that this protein is an important player in the UPR and defense against oxidative stress. ERMP1 expression is strongly affected by reticular stress induced by thapsigargin and other oxidative stresses. ERMP1 silencing during reticular stress impairs the activation of PERK, a key sensor of the UPR activation. Loss of ERMP1 also prevents the expression of GRP78/BiP, a UPR stress marker involved in the activation of the survival pathway. Finally, ERMP1 silencing in cells exposed to hypoxia leads to inhibition of the Nrf2-mediated anti-oxidant response and to reduction of accumulation of HIF-1, the master transcription factor instructing cells to respond to hypoxic stress. Our results suggest that ERMP1 could act as a molecular starter to the survival response induced by extracellular stresses. Moreover, they provide the rationale for the design of ERMP1-targeting drugs that could act by inhibiting the UPR initial adaptive response of cancer cells and impair cell survival
Pooled analysis of prognostic impact of urokinase-type plasminogen acticvator and its inhibitor PAI-1 in 8377 breast cancer patients.
Immunohistochemical evaluation of human epidermal growth factor receptor 2 and estrogen and progesterone receptors in breast carcinoma in Jordan
INTRODUCTION: Although breast carcinoma (BC) is the most common malignancy affecting Jordanian females and the affected population in Jordan is younger than that in the West, no information is available on its biological characteristics. Our aims in this study are to evaluate the expression of estrogen receptor (ER) and progesterone receptor (PR) and Her-2/neu overexpression in BC in Jordan, and to compare the expression of these with other prognostic parameters for BC such as histological type, histological grade, tumor size, patients' age, and number of lymph node metastases. METHOD: This is a retrospective study conducted in the Department of Pathology at Jordan University of Science and Technology. A confirmed 91 cases of BC diagnosed in the period 1995 to 1998 were reviewed and graded. We used immunohistochemistry to evaluate the expression of ER, PR, and Her-2. Immunohistochemical findings were correlated with age, tumor size, grade and axillary lymph node status. RESULTS: Her-2 was overexpressed in 24% of the cases. The mean age of Her-2 positive cases was 42 years as opposed to 53 years among Her-2 negative cases (p = 0.0001). Her-2 expression was inversely related to ER and PR expression. Her-2 positive tumors tended to be larger than Her-2 negative tumors with 35% overexpression among T3 tumors as opposed to 22% among T2 tumors (p = 0.13). Her-2 positive cases tended to have higher rates of axillary metastases, but this did not reach statistical significance. ER and PR positive cases were seen in older patients with smaller tumor sizes. CONCLUSION: Her-2 overexpression was seen in 24% of BC affecting Jordanian females. Her-2 overexpression was associated with young age at presentation, larger tumor size, and was inversely related to ER and PR expression. One-fifth of the carcinomas were Her-2 positive and ER negative. This group appears to represent an aggressive form of BC presenting at a young age with large primary tumors and a high rate of four or more axillary lymph node metastases
Pooled analysis of prognostic impact of urokinase-type plasminogen acticvator and its inhibitor PAI-1 in 8377 breast cancer patients.
Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in 8377 breast cancer patients
BACKGROUND: Urokinase-type plasminogen activator (uPA) and its inhibitor
(PAI-1) play essential roles in tumor invasion and metastasis. High levels
of both uPA and PAI-1 are associated with poor prognosis in breast cancer
patients. To confirm the prognostic value of uPA and PAI-1 in primary
breast cancer, we reanalyzed individual patient data provided by members
of the European Organization for Research and Treatment of Cancer-Receptor
and Biomarker Group (EORTC-RBG). METHODS: The study included 18 datasets
involving 8377 breast cancer patients. During follow-up (median 79
months), 35% of the patients relapsed and 27% died. Levels of uPA and
PAI-1 in tumor tissue extracts were determined by different immunoassays;
values were ranked within each dataset and divided by the number of
patients in that dataset to produce fractional ranks that could be
compared directly across datasets. Associations of ranks of uPA and PAI-1
levels with relapse-free survival (RFS) and overall survival (OS) were
analyzed by Cox multivariable regression analysis stratified by dataset,
including the following traditional prognostic variables: age, menopausal
status, lymph node status, tumor size, histologic grade, and steroid
hormone-receptor status. All P values were two-sided. RESULTS: Apart from
lymph node status, high levels of uPA and PAI-1 were the strongest
predictors of both poor RFS and poor OS in the analyses of all patients.
Moreover, in both lymph node-positive and lymph node-negative patients,
higher uPA and PAI-1 values were independently associated with poor RFS
and poor OS. For (untreated) lymph node-negative patients in particular,
uPA and PAI-1 included together showed strong prognostic ability (all
P<.001). CONCLUSIONS: This pooled analysis of the EORTC-RBG datasets
confirmed the strong and independent prognostic value of uPA and PAI-1 in
primary breast cancer. For patients with lymph node-negative breast
cancer, uPA and PAI-1 measurements in primary tumors may be especially
useful for designing individualized treatment strategies
Comparison of gene expression profiles in core biopsies and corresponding surgical breast cancer samples
INTRODUCTION: Gene expression profiling has been successfully used to classify breast cancer into clinically distinct subtypes, and to predict the risk of recurrence and treatment response. The aim of this study was to investigate whether the gene expression profile (GEP) detected in a core biopsy (CB) is representative for the entire tumor, since CB is an important tool in breast cancer diagnosis. Moreover, we investigated whether performing CBs prior to the surgical excision could influence the GEP of the respective tumor. METHODS: We quantified the RNA expression of 60 relevant genes by quantitative real-time PCR in paired CBs and surgical specimens from 22 untreated primary breast cancer patients. Subsequently, expression data were compared with independent GEPs obtained from tumors of 317 patients without preceding CB. RESULTS: In 82% of the cases the GEP detected in the CB correlated very well with the corresponding profile in the surgical sample (r(s )≥ 0.95, p < 0.001). Gene-by-gene analysis revealed four genes significantly elevated in the surgical sample compared to the CB; these comprised genes mainly involved in inflammation and the wound repair process as well as in tumor invasion and metastasis. CONCLUSION: A GEP detected in a CB are representative for the entire tumor and is, therefore, of clinical relevance. The observed alterations of individual genes after performance of CB deserve attention since they might impact the clinical interpretation with respect to prognosis and therapy prediction of the GEP as detected in the surgical specimen following CB performance
Differential survival following trastuzumab treatment based on quantitative HER2 expression and HER2 homodimers in a clinic-based cohort of patients with metastatic breast cancer
<p>Abstract</p> <p>Background</p> <p>We have recently described the correlation between quantitative measures of HER2 expression or HER2 homodimers by the HERmark assay and objective response (RR), time-to progression (TTP), and overall survival (OS) in an expanded access cohort of trastuzumab-treated HER2-positive patients with metastatic breast cancer (MBC) who were stringently selected by fluorescence in situ hybridization (FISH). Multivariate analyses suggested a continuum of HER2 expression that correlated with outcome following trastuzumab. Here we investigate the relationship between HER2 expression or HER2 homodimers and OS in a clinic-based population of patients with MBC selected primarily by IHC.</p> <p>Methods</p> <p>HERmark, a proximity-based assay designed to detect and quantitate protein expression and dimerization in formalin-fixed paraffin-embedded (FFPE) tissues, was used to measure HER2 expression and HER2 homodimers in FFPE samples from patients with MBC. Assay results were correlated with OS using univariate Kaplan-Meier, hazard function plots, and multivariate Cox regression analyses.</p> <p>Results</p> <p>Initial analyses revealed a parabolic relationship between continuous measures of HER2 expression and risk of death, suggesting that the assumption of linearity for the HER2 expression measurements may be inappropriate in subsequent multivariate analyses. Cox regression analyses using the categorized variable of HER2 expression level demonstrated that higher HER2 levels predicted better survival outcomes following trastuzumab treatment in the high HER2-expressing group.</p> <p>Conclusions</p> <p>These data suggest that the quantitative amount of HER2 expression measured by Hermark may be a new useful marker to identify a more relevant target population for trastuzumab treatment in patients with MBC.</p
Enhanced NFκB and AP-1 transcriptional activity associated with antiestrogen resistant breast cancer
BACKGROUND: Signaling pathways that converge on two different transcription factor complexes, NFκB and AP-1, have been identified in estrogen receptor (ER)-positive breast cancers resistant to the antiestrogen, tamoxifen. METHODS: Two cell line models of tamoxifen-resistant ER-positive breast cancer, MCF7/HER2 and BT474, showing increased AP-1 and NFκB DNA-binding and transcriptional activities, were studied to compare tamoxifen effects on NFκB and AP-1 regulated reporter genes relative to tamoxifen-sensitive MCF7 cells. The model cell lines were treated with the IKK inhibitor parthenolide (PA) or the proteasome inhibitor bortezomib (PS341), alone and in combination with tamoxifen. Expression microarray data available from 54 UCSF node-negative ER-positive breast cancer cases with known clinical outcome were used to search for potential genes signifying upregulated NFκB and AP-1 transcriptional activity in association with tamoxifen resistance. The association of these genes with patient outcome was further evaluated using node-negative ER-positive breast cancer cases identified from three other published data sets (Rotterdam, n = 209; Amsterdam, n = 68; Basel, n = 108), each having different patient age and adjuvant tamoxifen treatment characteristics. RESULTS: Doses of parthenolide and bortezomib capable of sensitizing the two endocrine resistant breast cancer models to tamoxifen were capable of suppressing NFκB and AP-1 regulated gene expression in combination with tamoxifen and also increased ER recruitment of the transcriptional co-repressor, NCoR. Transcript profiles from the UCSF breast cancer cases revealed three NFκB and AP-1 upregulated genes – cyclin D1, uPA and VEGF – capable of dichotomizing node-negative ER-positive cases into early and late relapsing subsets despite adjuvant tamoxfien therapy and most prognostic for younger age cases. Across the four independent sets of node-negative ER-positive breast cancer cases (UCSF, Rotterdam, Amsterdam, Basel), high expression of all three NFκB and AP-1 upregulated genes was associated with earliest metastatic relapse. CONCLUSION: Altogether, these findings implicate increased NFκB and AP-1 transcriptional responses with tamoxifen resistant breast cancer and early metastatic relapse, especially in younger patients. These findings also suggest that agents capable of preventing NFκB and AP-1 gene activation may prove useful in restoring the endocrine responsiveness of such high-risk ER-positive breast cancers
Genomic aberrations in normal tissue adjacent to HER2-amplified breast cancers: field cancerization or contaminating tumor cells?
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