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- Hedenfalk, Ingrid, et al.
(författare)
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Microarray-based Analyses of Hypoxia-induced Transcriptional Changes in Breast Cancer Cell Lines
- 2005
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Ingår i: Cancer Genomics & Proteomics. - 1790-6245. ; 2:2, s. 83-95
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Tidskriftsartikel (refereegranskat)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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- Kronblad, Åsa, et al.
(författare)
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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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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 24:45, s. 6835-6841
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Tidskriftsartikel (refereegranskat)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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- Rennstam, Karin, et al.
(författare)
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Genomic alterations in histopathologically normal breast tissue from BRCA1 mutation carriers may be caused by BRCA1 haploinsufficiency.
- 2010
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Ingår i: Genes, chromosomes & cancer. - : Wiley. - 1098-2264 .- 1045-2257. ; 49:1, s. 78-90
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Tidskriftsartikel (refereegranskat)abstract
- Multiple biopsies of normal breast tissue from 10 BRCA1 mutation carriers have been analyzed using array-based comparative genomic hybridization. Normal breast tissue from five age-matched control subjects without a family history of breast cancer was included for reference purposes. We repeatedly found multiple low copy number aberrations at a significantly higher frequency in histopathologically normal tissue from BRCA1 mutation carriers than in normal control tissue. Some of these aberrations were similar across samples from different patients and linked to biological functions such as transcriptional regulation and DNA binding. We also observed a high degree of genomic heterogeneity between samples from the same patient, suggestive of tissue heterogeneity and etiological clonality in the breast epithelium. We show that neither loss of heterozygosity nor promoter methylation of the wild-type BRCA1 allele is the predominant mechanistic origin of the observed genomic instability. Instead, we propose that haploinsufficiency of BRCA1 might be the underlying cause responsible for initiation of breast cancer in these predisposed women, making cells vulnerable to mitotic recombination. We also propose that loss of ERalpha expression is preceded by genetic instability in the initiation of BRCA1-dependent tumorigenesis, indicating that the breast epithelium of BRCA1 mutation carriers may initially be estrogen-responsive. Our results imply that genomic instability instigated by BRCA1 haploinsufficiency may be required for breast cancer initiation in BRCA1 mutation carriers. Finding molecular markers of tumor initiation and progression, for the potential use in early disease detection, may be of great clinical importance for the improved management of at-risk women.
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