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- Ekberg, Jenny, et al.
(author)
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Expression of cyclin A1 and cell cycle proteins in hematopoietic cells and acute myeloid leukemia and links to patient outcome
- 2005
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In: European Journal of Haematology. - : Wiley-Blackwell Publishing Inc.. - 0902-4441 .- 1600-0609. ; 75:2, s. 106-115
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Journal article (peer-reviewed)abstract
- Abnormal expression of several key regulators essential for G1/S transitions has been implicated in tumorigenesis. A critical role of cyclin A1 in the development of acute myeloid leukemia (AML) has previously been demonstrated in transgenic mice. Our present study focused on the expression and prognostic significance of cyclin A1 and a panel of cell cycle regulatory proteins including cyclin A2, cyclin B1, cyclin E, CDK1, CDK2, p21 and p27 in bone marrow samples from 40 patients with AML. Freshly isolated CD34+ hematopoietic cells and bone marrow samples from 10 healthy donors were also assessed for cell type- and subcellular-specific expression of the cell cycle regulatory proteins. The level of cyclin A1 expression was the only factor that showed a significant correlation with patient outcome. In log-rank test stratified by levels of cyclin A1 expression, patients with high levels of cyclin A1 had significantly worse overall survival (OS) (P = 0.012) compared to those with low levels. Further, patients with high levels of cyclin A1 had significantly lower disease-free survival (DFS) (P = 0.028). Multivariate analysis indicated that cyclin A1 protein expression was an independent prognostic factor for predicting DFS (P = 0.035) and OS (P = 0.045). No correlation between cyclin A1 expression and age was found. However, expression of cyclin A2, cyclin B1, cyclin E, CDK1, CDK2, p21 and p27 did not show prognostic significance in these AML patients.
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- Hedenfalk, Ingrid, et al.
(author)
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Microarray-based Analyses of Hypoxia-induced Transcriptional Changes in Breast Cancer Cell Lines
- 2005
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In: Cancer Genomics & Proteomics. - 1790-6245. ; 2:2, s. 83-95
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Journal article (peer-reviewed)abstract
- Background: Tumour hypoxia is a common characteristic of many solid human tumours, and is associated with a poor prognosis in various types of cancer. Metabolic changes occur when cells are exposed to low oxygen pressure; however, little is known about the mechanisms underlying malignant transformation and/or progression caused by hypoxia. Materials and Methods: We monitored global gene expression changes caused by hypoxia in four breast cancer cell lines using 27K cDNA microarrays. Cells were grown under hypoxic and normoxic conditions, and were harvested at four different time points. All genes were assigned to patterns (up, down, or unchanged) across the time points, followed by ontological mapping to investigate significant associations between genes belonging to specific patterns and Gene Ontology categories. Furthermore, we investigated genomic regions upstream of regulated genes for the presence of known regulatory motifs. Results: Several common effects of hypoxia were seen in the breast cancer cell lines, such as an increase in glycolytic metabolism; however, the response to hypoxia varied greatly between the cell lines. Oestrogen receptor (ER)-positive breast cancer cells displayed a partially unique response to hypoxia compared to ER-negative cells. Similarly, unique changes in e.g. RNA metabolism and DNA repair were seen in a BRCA1-deficient cell line. Whereas an enrichment of genes containing the HIF-1 binding site sequence was found among genes regulated by hypoxia in two of the cell lines investigated, this sequence was also identified in a considerable fraction of non-regulated genes. Conclusion: Global gene expression profiling of the cellular response to hypoxia revealed a multitude of novel mechanisms and functions affected by hypoxia in breast cancer cell lines. The findings also suggest a high degree of diversity in this response depending on the genetic background of the tumour cells. Specifically, down-regulation of genes involved in DNA repair mechanisms in a BRCA1-deficient cell line may reflect the crucial role played by the BRCA1 protein in instances of DNA damage, e.g. during hypoxia.
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- Jirström, Karin, et al.
(author)
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Adverse effect of adjuvant tamoxifen in premenopausal breast cancer with cyclin D1 gene amplification
- 2005
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In: Cancer Research. - 0008-5472 .- 1538-7445. ; 65:17, s. 8009-8016
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Journal article (peer-reviewed)abstract
- Cyclins D1 and A2 are cell cycle regulators that also have the ability to interact with the estrogen receptor (ER) and consequently interfere with antiestrogen treatment in breast cancer. Experimental data support this concept, but the clinical relevance needs to be further established. In this study, we evaluated cyclin D1 and A2 protein expression by immunohistochemistry and cyclin D1 gene (CCND1) amplification by fluorescence in situ hybridization in 500 primary breast cancers arranged in tissue microarrays. Patients had been randomized to 2 years of adjuvant tamoxifen or no treatment with a median follow-up of 14 years, allowing for subgroup analysis of treatment response defined by cyclin status. We found that both cyclin D1 and A2 protein overexpression was associated with an impaired tamoxifen response, although not significant in multivariate interaction analyses, whereas tamoxifen-treated patients with CCND1-amplified tumors had a substantially increased risk for disease recurrence after tamoxifen treatment in univariate analyses [relative risk (RR), 2.22; 95% confidence interval (95% CI), 0.94-5.26; P = 0.06] in contrast to nonamplified tumors (RR, 0.39; 95% CI, 0.23-0.65; P < 0.0001). Consequently, a highly significant interaction between tamoxifen treatment and CCND1 amplification could be shown regarding both recurrence-free survival (RR, 6.38; 95% CI, 2.29-17.78; P < 0.001) and overall survival (RR, 5.34; 95% CI, 1.84-15.51; P = 0.002), suggesting an agonistic effect of tamoxifen in ER-positive tumors. In node-positive patients, the disparate outcome according to gene amplification status was even more accentuated. In summary, our data implicate that despite a significant correlation to cyclin D1 protein expression, amplification status of the CCND1 gene seems a strong independent predictor of tamoxifen response, and possibly agonism, in premenopausal breast cancer.
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- Jirström, Karin, et al.
(author)
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Pathology parameters and adjuvant tamoxifen response in a randomised premenopausal breast cancer trial
- 2005
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In: Journal of Clinical Pathology. - : BMJ. - 0021-9746 .- 1472-4146. ; 58:11, s. 1135-1142
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Journal article (peer-reviewed)abstract
- Background: Subgroups of breast cancer that have an impaired response to endocrine treatment, despite hormone receptor positivity, are still poorly defined. Breast cancer can be subdivided according to standard pathological parameters including histological type, grade, and assessment of proliferation. These parameters are the net result of combinations of genetic alterations effecting tumour behaviour and could potentially reflect subtypes that respond differently to endocrine treatment.Aims: To investigate the usefulness of these parameters as predictors of the response to tamoxifen in premenopausal women with breast cancer.Materials/methods: Clinically established pathological parameters were assessed and related to the tamoxifen response in 500 available tumour specimens from 564 premenopausal patients with breast cancer randomised to either two years of tamoxifen or no treatment with 14 years of follow up. Proliferation was further evaluated by immunohistochemical Ki-67 expression.Results: Oestrogen receptor positive ductal carcinomas responded as expected to tamoxifen, whereas the difference in recurrence free survival between control and tamoxifen treated patients was less apparent in the relatively few lobular carcinomas. For histological grade, there was no obvious difference in treatment response between the groups. The relation between proliferation and tamoxifen response seemed to be more complex, with a clear response in tumours with high and low proliferation, whereas tumours with intermediate proliferation defined by Ki-67 responded more poorly.Conclusions: Clinically established pathology parameters seem to mirror the endocrine treatment response and could potentially be valuable in future treatment decisions for patients with breast cancer.
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- Kronblad, Åsa, et al.
(author)
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ERK1/2 inhibition increases antiestrogen treatment efficacy by interfering with hypoxia-induced downregulation of ERalpha: a combination therapy potentially targeting hypoxic and dormant tumor cells.
- 2005
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In: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 24:45, s. 6835-6841
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Journal article (peer-reviewed)abstract
- Tumor hypoxia is associated with cancer invasiveness, metastasis and treatment failure. Recent data suggest that the major target for endocrine treatment in breast cancer, ER alpha, is downregulated during hypoxia, but the mechanism behind this remains unknown. MAPK signaling as well as ER alpha regulation has earlier been independently linked to hypoxia and we now demonstrate HIF-1 alpha and ERK1/2-activation in vivo towards the necrotic zone in DCIS of the breast, parallel with ER alpha downregulation. Hypoxia further caused transcriptional downregulation of ER alpha via activation of ERK1/2 in cell lines and, importantly, MEK1/2 inhibitors (U0126 or PD184352) or ERK1/2 suppression by siRNA partially restored the ERa expression. U0126 combined with tamoxifen accordingly produced an increased efficacy of the anti-estrogens during hypoxia. Base don these findings, we suggest a promising novel therapy for ER alpha-positive breast cancer where a combination of endocrine treatment and ERK1/2 inhibitors may increase treatment response by improved targeting of dormant hypoxic tumor cells.
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- Lörinc, Ester, et al.
(author)
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Ki67 and p53 immunohistochemistry reduces interobserver variation in assessment of Barrett's oesophagus.
- 2005
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In: Histopathology. - : Wiley. - 0309-0167 .- 1365-2559. ; 46:6, s. 642-648
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Journal article (peer-reviewed)abstract
- Aims: To devise clinically applicable methods for assessing p53 and Ki67 immunohistochemical (IHC) reactivity in Barrett's oesophagus (BE) and to compare the interobserver agreement between these methods and routine haematoxylin and eosin (H&E) evaluation. Methods and results: One hundred and fifteen biopsies diagnosed as BE, selected from the files of the University Hospital MAS, Malmö, were re-evaluated for dysplasia by three pathologists. For IHC analysis areas with the most prominent positivity were evaluated. The mean of p53+ epithelial nuclei/high-power field (HPF) was obtained by counting between 1 and 5 HPFs/biopsy. A proliferation quotient (PQ) was obtained by dividing the number of Ki67+ epithelial nuclei in the upper half by the lower half of the mucosa, using two HPFs. Mean κ values were 0.24, 0.71 and 0.52 for H&E, p53 and Ki67 evaluations, respectively. There was a correlation between increasing severity of dysplasia, IHC measurable overexpression of p53 and shift of the mucosal proliferation zone towards the surface, measured as PQ. Conclusions: The described methods for p53 and Ki67 evaluation are more reproducible than routine H&E evaluation of BE. Furthermore, the IHC methods correlate with the severity of dysplasia and are useful supplementary prognostic markers.
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