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- Ahnström Waltersson, Marie, 1976-
(author)
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Cell cycle alterations and 11q13 amplification in breast cancer : prediction of adjuvant treatment response
- 2009
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Doctoral thesis (other academic/artistic)abstract
- The growth and development of the breast is to a large extent regulated by oestrogens through the oestrogen receptor (ER). Activation of the ERα triggers transcription of genes that are important for cell proliferation and stimulates entry into the G1 phase of the cell cycle. In breast cancer the ERα is often upregulated and is therefore a suitable target for adjuvant therapies such as tamoxifen. Although tamoxifen is an effective treatment in most cases, tumours sometimes acquire resistance to the drug. The aim of this thesis was to investigate the impact of G1 phase proteins and 11q13 amplification on prognosis and treatment response in breast cancer. The material used was from a clinical trial in which postmenopausal breast cancer patients were randomised to chemotherapy or radiotherapy and tamoxifen or no adjuvant treatment. We studied the expression of cyclin D1, cyclin E and Rb with immunohisochemistry and amplification of CCND1 and PAK1 with real time PCR. We found that among patients with high tumour expression of cyclin D1, overexpression of ErbB2 was associated with reduced recurrence-free survival. Both cyclin D1 and cyclin E overexpression were associated with reduced tamoxifen response. High expression of cyclin D1 has been found to induce ligand independent activation of ERα in breast cancer cells and might also switch tamoxifen from acting as an antagonist to an agonist. Overexpression of cyclin E has been shown to be associated with expression of low molecular weight isoforms of the protein that possess an increased kinase activity and are insensitive to p21 and p27 inhibition. Furthermore, amplification of 11q13, and in particular the gene PAK1, was a strong predictor of tamoxifen resistance. The pak1 protein is involved in phosphorylation and ligand independent activation of the ERα. We also found that lost expression of either p53 or Rb reduced the patients benefit from radiotherapy compared with patients with normal expression of both proteins. Normally, ionizing radiation upregulates p53 resulting in G1 arrest or apoptosis. If either functional p53 or Rb is missing the cells can proceed from G1 to the S phase despite damaged DNA. The expression of the microRNA, miR-206, was analysed with real time PCR, and the results showed that high expression of miR-206 correlated to low expression of ERα and 11q13 amplification. In vitro studies have shown that miR-206 negatively regulates the expression of ERα. Taken together the G1 regulators and amplification of 11q13 seem to have an important role in predicting the patient’s response to adjuvant therapy.
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| 2. |
- Ahnström Waltersson, Marie, 1976-, et al.
(author)
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miR-206 expression is downregulated in cyclin D1 amplified breast tumours
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Other publication (other academic/artistic)abstract
- Amplification in the 11q13 region has been found in around 15% of all breast cancers and is strongly correlated with oestrogen receptor (ER) positive tumours. We have previously found that amplification of at least one of the genes PAK1 or CCND1 is associated with decreased recurrencefree survival among ER+ patients. Other genes in the amplicon might also contribute to this effect and situated close to CCND1 are the FGF-3, -4 and - 19 genes. The FGF-4 protein has been shown to inhibit the expression of the ERα regulator miR-206 in chicken embryo. In this study we analysed 23 tumours with and 27 tumours without previously detected 11q13 amplification to explore if 11q13 amplification is associated with decreased levels of miR-206 and if miR-206 is associated with ER expression. Using real-time PCR, we found that miR-206 expression was inversely correlated to CCND1 and 11q13 amplification (P=0.016 and P=0.022 respectively). Tumours with low miR-206 expression had higher levels of ERα than tumours with intermediate and high expression (P=0.043). We conclude that miR-206 might be an important regulator of the ERα. Our finding that low mir-206 is associated with CCND1 amplification and thereby also FGF-4 amplification points towards the possibility of a miR-206 regulator, FGF-4 or another FGF, present in the amplicon.
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| 3. |
- Ahnström Waltersson, Marie, 1976-, et al.
(author)
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Role of cyclin D1 in ErbB2-positive breast cancer and tamoxifen resistance.
- 2005
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In: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 0167-6806 .- 1573-7217. ; 91:2, s. 145-151
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Journal article (peer-reviewed)abstract
- Cyclin D1 plays an important role in the regulation of the G1 phase in the cell cycle. In mammary epithelial cells the expression of cyclin D1 is regulated through the oestrogen receptor and via ErbB2 signalling. Here we investigated the prognostic significance of cyclin D1 among 230 breast cancer patients randomised for tamoxifen, CMF chemotherapy and radiotherapy. The importance of combined cyclin D1 and ErbB2 overexpression was also analysed. Immunohistochemical analysis of the cyclin D1 expression resulted in 69 (29.8%) weakly positive, 107 (46.5%) moderately positive and 54 (23.7%) strongly positive cases. The prognostic importance of ErbB2 was significantly greater for patients whose tumours overexpressed cyclin D1 than for other patients (p = 0.026). In the former group, ErbB2 overexpression was strongly associated with increased risk of recurrence (RR = 4.7; 95% CI, 2.1-10.4) and breast cancer death (RR = 5.4; 95% CI, 2.3-12.6). This result is in accordance with experimental studies demonstrating a link between cyclin D1 and ErbB2 in oncogenesis. Among oestrogen receptor positive patients, those with moderate cyclin D1 expression significantly did benefit from tamoxifen treatment (RR = 0.42; 95% CI, 0.21-0.82) whereas those with weak or strong expression did not. Therefore cyclin D1 might be a predictive marker for tamoxifen resistance.
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| 4. |
- Bergman, Malin, 1967-, et al.
(author)
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Polymorphism in the manganese superoxide dismutase (MnSOD) gene and risk of breast cancer in young women
- 2005
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In: Journal of Cancer Research and Clinical Oncology. - : Springer Science and Business Media LLC. - 0171-5216 .- 1432-1335. ; 131:7, s. 439-444
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Journal article (peer-reviewed)abstract
- Purpose: Manganese superoxide dismutase (MnSOD) is one of the major enzymes implicated in the cellular defence against reactive oxygen species. Low expression of MnSOD has been observed in different cancer tissues and several reports have shown that overexpression of MnSOD inhibits growth in various human cancer cells. These observations suggest that MnSOD is involved in carcinogenesis. A polymorphism (Ala-9Val) in the mitochondrial targeting sequence (MTS) of the MnSOD gene has been proposed to affect protein localization and thereby influence cellular defence against superoxide radicals.Methods: In the present case-control study, including 118 early onset breast cancer patients (≤36 years) and 174 age-matched controls, the MTS polymorphism and loss of heterozygosity (LOH) in the locus of MnSOD were analysed.Results: We found that individuals with MnSODVal/Val and MnSODVal/Ala genotypes showed an increased risk of breast cancer (OR, 2.7; 95% CI, 2.2–5.5, p=0.01, OR, 3.0; 95%CI, 1.4–6.5, p=0.002). Moreover, 45% of the informative cases expressed allelic loss at the chromosomal locus of the MnSOD gene. No correlation was found between LOH and the genotype.Conclusion: The present study suggests that MnSOD may be implicated in breast carcinogenesis in young women.
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| 5. |
- Gentile, Massimiliano, et al.
(author)
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Candidate tumour suppressor genes at 11q23-q24 in breast cancer : evidence of alterations in PIG8, a gene involved in p53-induced apoptosis
- 2001
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In: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 20:53, s. 7753-7760
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Journal article (peer-reviewed)abstract
- One of the most consistently deleted chromosomal regions in solid tumours is 11q23-q25, which consequently has been postulated to harbour one or more tumour suppressor loci. Despite large efforts to identify the responsible genes, the goal remains elusive, but as knowledge accumulates new candidates are emerging. The present study was undertaken in an attempt to assess the possible implication of four genes residing at 11q23-q24, in a population of early onset breast cancer (n=41). The coding sequence of PIG8, CHK1, LOH11CR2A and PPP2R1B were screened for mutations using the protein truncation test or single-strand conformational polymorphism, in combination with direct DNA sequencing. Varying proportions of alterations were detected, ranging from 6% in PPP2R1B to 39% in PIG8. Many of these changes were deletions, in some cases corresponding to complete exons, thus likely to represent splice variants, while others were presumed to arise from aberrant splicing, since they occurred at sites with resemblance to exon/intron borders. Considering only bona fide mutations, the highest alteration frequency (17%) was again found in PIG8. Most of these alterations were likely to have an adverse impact on the translated protein as they either altered the reading frame or affected phylogenetically conserved residues. Our data represent the first evidence of alterations in the PIG8 gene in human malignancies, a finding that substantiates its role as a potential tumour suppressor gene as suggested by its involvement in p53-induced apoptosis.
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| 6. |
- Gunnarsson, Cecilia, 1970-, et al.
(author)
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Amplification of HSD17B1 and ERBB2 in primary breast cancer
- 2003
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In: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 22:1, s. 34-40
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Journal article (peer-reviewed)abstract
- Estrogens play a crucial role in the development of breast cancer. Estradiol can be produced in the breast tissue in situ, and one of the enzymes involved in this process is 17β-hydroxysteriod dehydrogenase (17β-HSD) type 1 that catalyzes the interconversion of estrone (E1) to the biologically more potent estradiol (E2). The gene coding for 17β-HSD type 1 (HSD17B1) is located at 17q12-21, close to the more studied ERBB2 and BRCA1. The aim of this study was to investigate if HSD17B1 shows an altered gene copy number in breast cancer. We used real-time PCR and examined 221 postmenopausal breast tumors for amplification of HSD17B1 and ERBB2. In all, 32 tumors (14.5%) showed amplification of HSD17B1 and 21% were amplified for ERBB2. Amplification of the two genes was correlated (P = 0.00078) and in 14 tumors (44%) with amplification of HSD17B1, ERBB2 was co amplified. The patients with amplification in at least one of the genes had a significantly worse outcome than patients without (P = 0.0059). For estrogen receptor (ER)-positive patients who received adjuvant tamoxifen, amplification of HSD17B1 was related to decreased breast cancer survival (P = 0.017), whereas amplification of ERRB2 was not. Amplification of HSD17B1 might be an indicator of adverse prognosis among ER-positive patients, and possibly a mechanism for decreased benefit from tamoxifen treatment.
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| 7. |
- Yu, Qunyan, et al.
(author)
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Requirement for CDK4 kinase function in breast cancer
- 2006
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In: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 9:1, s. 23-32
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Journal article (peer-reviewed)abstract
- Cyclin D1 is overexpressed in the majority of human breast cancers. We previously found that mice lacking cyclin D1 are resistant to mammary carcinomas triggered by the ErbB-2 oncogene. In this study, we investigated which function of cyclin D1 is required for ErbB-2-driven mammary oncogenesis. We report that the ability of cyclin D1 to activate cyclin-dependent kinase CDK4 underlies the critical role for cyclin D1 in breast cancer formation. We also found that the continued presence of CDK4-associated kinase activity is required to maintain breast tumorigenesis. We analyzed primary human breast cancers and found high cyclin D1 levels in a subset (∼25%) of ErbB-2-overexpressing tumors. We propose that this subset of breast cancer patients might benefit from inhibiting CDK4 kinase.
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