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- Aaltonen, Kirsimari, et al.
(författare)
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Cyclin D1 expression is associated with poor prognostic features in estrogen receptor positive breast cancer
- 2009
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Ingår i: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 1573-7217 .- 0167-6806. ; 113:1, s. 75-82
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Tidskriftsartikel (refereegranskat)abstract
- Cyclins D1 and E play an important role in breast carcinogenesis. High cyclin E expression is common in hormone receptor negative and high grade aggressive breast cancer, whereas cyclin D1 in hormone receptor positive and low grade breast cancer. Experimental data has suggested that cyclin D1 and E mediate cell proliferation by different mechanisms in estrogen receptor (ER) positive and negative breast cancer. To test this hypotheses in large breast cancer material and to clarify the histopathological correlations of cyclin E and D1, especially the association with proliferation, we analyzed cyclin E and D1 immunohistochemical expression on breast tumour microarrays consisting of 1348 invasive breast cancers. High cyclin D1 expression was associated with high grade (P < 0.0005), high cyclin A (P < 0.0005) and Ki67 (P < 0.0005) expression among ER positive but with low grade (P = 0.05) and low Ki67 (P = 0.01) expression among ER negative breast cancers. Cyclin E and D1 expression correlated positively in ER positive (P < 0.0005) but had a negative correlation in ER negative tumours (P = 0.004). Cyclin E associated with high grade among all tumours (P < 0.0005). In conclusion, the findings of this study show that cyclin D1 has separate roles, and proliferation is driven by different mechanisms in ER positive and negative breast cancers.
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| 2. |
- Aaltonen, Kirsimari, et al.
(författare)
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Familial breast cancers without mutations in BRCA1 or BRCA2 have low cyclin E and high cyclin D1 in contrast to cancers in BRCA mutation carriers
- 2008
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 14:7, s. 1976-83
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: We analyzed the expression of critical cell cycle regulators cyclin E and cyclin D1 in familial breast cancer, focusing on BRCA mutation-negative tumors. Cyclin E expression in tumors of BRCA1 or BRCA2 carriers is higher, and cyclin D1 expression lower, than in sporadic tumors. In familial non-BRCA1/2 tumors, cyclin E and cyclin D1 expression has not been studied. EXPERIMENTAL DESIGN: Cyclin E and cyclin D1 immunohistochemical expression was studied in tissue microarrays consisting of 53 BRCA1, 58 BRCA2, 798 familial non-BRCA1/2, and 439 sporadic breast tumors. RESULTS: In univariate analysis, BRCA1 tumors had significantly more frequently high cyclin E (88%) and low cyclin D1 (84%) expression than sporadic (54% and 49%, respectively) or familial non-BRCA1/2 (38% and 45%, respectively) tumors. BRCA2 tumors had significantly more frequently low cyclin D1 expression (68%) than sporadic or familial non-BRCA1/2 tumors and significantly more frequently high cyclin E expression than familial non-BRCA1/2 tumors. In a logistic regression model, cyclin expression, early age of onset, and estrogen receptor (ER) and human epidermal growth factor receptor-2 (HER2) status were the independent factors most clearly distinguishing tumors of BRCA1 mutation carriers from other familial breast cancers. High cyclin E and low cyclin D1 expression were also independent predictors of BRCA2 mutation when compared with familial non-BRCA1/2 tumors. Most interestingly, lower frequency of high cyclin E expression independently distinguished familial non-BRCA1/2 tumors also from sporadic ones. CONCLUSIONS: Cyclin E and cyclin D1 expression distinguishes non-BRCA1/2 tumors from both sporadic and BRCA1- and BRCA2-associated tumors and may reflect different predisposition and pathogenesis in these groups.
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| 3. |
- Eerola, Hannaleena, et al.
(författare)
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Basal cytokeratins in breast tumours among BRCA1, BRCA2 and mutation-negative breast cancer families
- 2008
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Ingår i: Breast cancer research : BCR. - : Springer Science and Business Media LLC. - 1465-542X. ; 10:1, s. R17-
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Finding new immunohistochemical markers that are specific to hereditary breast cancer could help us to select candidates for BRCA1/BRCA2 mutation testing and to understand the biological pathways of tumour development. METHODS: Using breast cancer tumour microarrays, immunohistochemical expression of cytokeratin (CK)-5/6, CK-14 and CK-17 was evaluated in breast tumours from BRCA1 families (n = 46), BRCA2 families (n = 40), non-BRCA1/BRCA2 families (n = 358) and familial breast cancer patients with one first-degree relative affected by breast or ovarian cancer (n = 270), as well as from patients with sporadic breast cancer (n = 364). Staining for CK-5/6, CK-14 and CK-17 was compared between these groups and correlated with other clinical and histological factors. RESULTS: CK-5/6, CK-14 and CK-17 were detected mostly among oestrogen receptor (ER)-negative, progesterone receptor (PR)-negative and high-grade tumours. We found the highest percentages of samples positive for these CKs among ER-negative/HER2-negative tumours. In univariate analysis, CK-14 was significantly associated with tumours from BRCA1 (39%; P < 0.0005), BRCA2 (27%; P = 0.011), and non-BRCA1/BRCA2 (21%; P < 0.005) families, as compared with sporadic tumours (10%). However, in multivariate analysis, CKs were not found to be independently associated with BRCA1 or BRCA2 mutation status, and the most effective predictors of BRCA1 mutations were age at onset, HER2 status, and either ER or PR status. CONCLUSION: Although our study confirms that basal CKs can help to identify BRCA1 mutation carriers, this effect was weaker than previously suggested and CKs did not independently predict BRCA1 mutation either from sporadic or familial breast cancer cases. The most effective, independent predictors of BRCA1 mutations were age at onset, HER2 status, and either ER or PR status, as compared with sporadic or non-BRCA1/BRCA2 cancers.
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| 6. |
- Johannsdottir, Hrefna K., et al.
(författare)
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Chromosome 5 imbalance mapping in breast tumors from BRCA1 and BRCA2 mutation carriers and sporadic breast tumors
- 2006
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 119:5, s. 1052-1060
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Tidskriftsartikel (refereegranskat)abstract
- Comparative genomic hybridization (CGH) analysis has shown that chromosome 5q deletions are the most frequent aberration in breast tumors from BRCA1 mutation carriers. To map the location of putative 5q tumor suppressor gene(s), 26 microsatellite markers covering chromosome 5 were used in loss of heterozygosity (LOH) analysis of breast tumors from BRCA1 (n = 42) and BRCA2 mutation carriers (n = 67), as well as in sporadic cases (n = 65). High, density array CGH was also used to map chromosome 5 imbalance in 10 BRCA1 tumors. A high LOH frequency was found in BRCA1 tumors (range 19-82%), as compared to BRCA2 and sporadic tumors (ranges 11-44% and 7-43%, respectively). In all, 11 distinct chromosome 5 regions with LOH were observed, the most frequent being 5q35.3 (82%), 5q14.2 (71%) and 5q33.1 (69%) in BRCA1 tumors; 5q35.3 (44%), 5q31.3 (43%) and 5q13.3 (43%) in BRCA2 tumors and 5q31.3 (43%) in sporadic tumors. Array CGH analysis confirmed the very high frequency of 5q deletions, including candidate tumor suppressor genes such as XRCC4, RAD50, RASA1, APC and PPP2R2B. In addition, 2 distinct homozygous deletions were identified, spanning regions of 0.7-1.5 Mbp on 5q12.1 and 5q12.3-q13.1, respectively. These regions include only a few genes, most notably BRCC3/DEPDC1B (pleckstrin/G protein interacting and RhoGAP domains) and PIK3R1 (PI3 kinase P85 regulatory subunit). Significant association (p <= 0.05) was found between LOH at certain 5q regions and factors of poor prognosis, including negative estrogen and progesterone receptor status, high grade, large tumor size and high portion of cells in S-phase. In conclusion, our results confirm a very high prevalence of chromosome 5q alterations in BRCA1 tumors, pinpointing new regions and genes that should be further investigated. (c) 2006 Wiley-Liss, Inc.
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| 7. |
- Kainu, T, et al.
(författare)
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Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus
- 2000
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Ingår i: Proceedings of the National Academy of Sciences. - 1091-6490. ; 97:17, s. 9603-9608
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Tidskriftsartikel (refereegranskat)abstract
- A significant proportion of familial breast cancers cannot be explained by mutations in the BRCA1 or BRCA2 genes. We applied a strategy to identify predisposition loci for breast cancer by using mathematical models to identify early somatic genetic deletions in tumor tissues followed by targeted linkage analysis. Comparative genomic hybridization was used to study 61 breast tumors from 37 breast cancer families with no identified BRCA1 or BRCA2 mutations. Branching and phylogenetic tree models predicted that loss of 13q was one of the earliest genetic events in hereditary cancers. In a Swedish family with five breast cancer cases, all analyzed tumors showed distinct 13q deletions, with the minimal region of loss at 13q21-q22. Genotyping revealed segregation of a shared 13q21 germ-line haplotype in the family. Targeted linkage analysis was carried out in a set of 77 Finnish, Icelandic, and Swedish breast cancer families with no detected BRCA1 and BRCA2 mutations. A maximum parametric two-point logarithm of odds score of 2.76 was obtained for a marker at 13q21 (D13S1308, theta = 0.10). The multipoint logarithm of odds score under heterogeneity was 3.46. The results were further evaluated by simulation to assess the probability of obtaining significant evidence in favor of linkage by chance as well as to take into account the possible influence of the BRCA2 locus, located at a recombination fraction of 0.25 from the new locus. The simulation substantiated the evidence of linkage at D13S1308 (P < 0.0017). The results warrant studies of this putative breast cancer predisposition locus in other populations.
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