| 1. |
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| 2. |
- Borgquist, Signe, et al.
(författare)
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Oestrogen receptors alpha and beta show different associations to clinicopathological parameters and their co-expression might predict a better response to endocrine treatment in breast cancer.
- 2008
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Ingår i: Journal of Clinical Pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 61:2, s. 197-202
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: The majority of all breast cancers are hormone responsive, traditionally defined by the expression of oestrogen receptor (ER) alpha and/or progesterone receptors. In contrast to ERalpha, the clinical significance of the relatively recently identified ERbeta is still unclear. This study aimed to define the relationship between ERbeta and clinicopathological parameters in a mixed cohort of breast cancer and, furthermore, to investigate the impact of ERbeta expression on disease outcome. METHODS: The immunohistochemical expression of ERalpha and ERbeta was analysed in tissue microarrays containing a total number of 512 tumours with all incident breast cancers diagnosed at the Malmö University Hospital between 1988 and 1992. RESULTS: 78% of the tumours were ERalpha positive and 50% were ERbeta positive. ERbeta correlated positively with ERalpha (p = 0.001). In contrast to ERalpha, ERbeta was not associated with any important clinicopathological variables. Furthermore, no overall prognostic significance could be demonstrated for ERbeta. In the ERalpha-positive subgroup, however, a low expression of ERbeta correlated with a decreased disease-free survival in patients receiving endocrine treatment (p = 0.003). CONCLUSIONS: Although interrelated, ERalpha and ERbeta seem to be differentially associated to clinicopathological parameters, and this would support the fact that they might have different functions in vivo. Furthermore, ERbeta might be a predictive marker of response to endocrine therapy, although this needs to be confirmed in additional studies, preferably randomised trials.
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| 3. |
- Ekberg, Jenny, et al.
(författare)
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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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Ingår i: European Journal of Haematology. - : Wiley-Blackwell Publishing Inc.. - 0902-4441 .- 1600-0609. ; 75:2, s. 106-115
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Tidskriftsartikel (refereegranskat)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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| 4. |
- Ekberg, Jenny, et al.
(författare)
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Regulation of the cyclin A1 protein is associated with its differential subcellular localization in hematopoietic and leukemic cells
- 2004
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Ingår i: Oncogene. - : Nature Publishing Group. - 0950-9232 .- 1476-5594. ; 23:56, s. 9082-9089
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Tidskriftsartikel (refereegranskat)abstract
- An important role of the cell cycle regulatory protein cyclin A1 in the development of acute myeloid leukemia (AML) was previously demonstrated in a transgenic mouse model. We have now turned our attention to study specific aspects of the activity and subcellular distribution of cyclin A1 using bone marrow samples from normal donors and patients with AML, as well as leukemic cell lines. We show that the localization of cyclin A1 in normal hematopoietic cells is nuclear, whereas in leukemic cells from AML patients and cell lines, it is predominantly cytoplasmic. In leukemic cell lines treated with all-trans retinoic acid (ATRA), cyclin A1 localized to the nucleus. Further, there was a direct interaction between cyclin A1 and cyclin-dependent kinase 1, as well as a major ATRA receptor, RARalpha, in ATRA-treated cells but not in untreated leukemic cells. Our results indicate that the altered intracellular distribution of cyclin A1 in leukemic cells correlates with the status of the leukemic phenotype.
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| 5. |
- Gururaj, Anupama E, et al.
(författare)
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Breast cancer-amplified sequence 3, a target of metastasis-associated protein 1, contributes to tamoxifen resistance in premenopausal patients with breast cancer
- 2006
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Ingår i: Cell Cycle. - 1551-4005. ; 5:13, s. 1407-1410
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Tidskriftsartikel (refereegranskat)abstract
- Lysine acetylation occurs in many protein targets, including core histones, transcription factors, and other proteins. Metastasis-associated protein 1 (MTA1) is implicated in the progression and metastasis of various epithelial tumors. Because MTA1 functions as a transcriptional coregulator, much of its role in cancer promoting processes are likely to involve its ability to regulate the transcription of downstream target genes that encode effector proteins. We recently showed that MTA1 could be post-translationally modified by acetylation, which modulates its function as a coregulator molecule. We also defined a chromatin target of MTA1, namely, breast cancer-amplified sequence 3 (BCAS3), in the context of which MTA1 behaves as a transcriptional coactivator in breast cancer cells. Because the phenotypic effect of BCAS3 overexpression in tumors has not been defined, we investigated the consequence of increased expression of BCAS3 in human breast tumors. Here, we report that BCAS3 overexpression in hormone receptor-positive premenopausal breast cancer seemed to be associated with impaired responses to tamoxifen. Our findings have implications for endocrine therapy.
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| 6. |
- Gururaj, AE, et al.
(författare)
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MTA1, a transcriptional activator of breast cancer amplified sequence 3
- 2006
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 103:17, s. 6670-6675
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Tidskriftsartikel (refereegranskat)abstract
- Here we define a function of metastasis-associated protein 1 (MTA1), a presumed corepressor of estrogen receptor alpha (ER alpha), as a transcriptional activator of Breast Cancer Amplified Sequence 3 (BCAS3), a gene amplified and overexpressed in breast cancers. We identified BCAS3 as a MTA1 chromatin target in a functional genomic screen. MTA1 stimulation of BCAS3 transcription required ERa and involved a functional ERE half-site in BCAS3. Furthermore, we discovered that MTA1 is acetylated on lysine 626, and that this acetylation is necessary for a productive transcriptional recruitment of RNA polymerase 11 complex to the BCAS3 enhancer sequence. BCAS3 expression was elevated in mammary tumors from MTA1 transgenic mice and 60% of the human breast tumors, and correlated with the coexpression of MTA1 as well as with tumor grade and proliferation of primary breast tumor samples. These findings reveal a previously unrecognized function of MTA1 in stimulating BCAS3 expression and suggest an important role for MTA1-BCAS3 pathway in promoting cancerous phenotypes in breast tumor cells.
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| 7. |
- Holm, Caroline, et al.
(författare)
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Cyclin A1 expression and associations with disease characteristics in childhood acute lymphoblastic leukemia
- 2006
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Ingår i: Leukemia Research. - : Elsevier. - 0145-2126 .- 1873-5835. ; 30:3, s. 254-261
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Tidskriftsartikel (refereegranskat)abstract
- A critical cell cycle regulatory protein, cyclin A1, has been implicated in the development of acute myeloid leukemia (AML). Here, we have examined the expression and clinical significance of cyclin A1 in childhood acute lymphoblastic leukemia (ALL). Cyclin A1 was highly expressed in lymphoblastic leukemic cell lines and in 22 of 30 ALL patients (73%). Cyclin A1 expression correlated with patient age (P=0.006), but not with cytogenetic abnormalities. Patients with high levels of cyclin A1 had poorer event-free survival (57.9%) compared to patients with lower levels (75%).
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| 8. |
- Holm, C, et al.
(författare)
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Phosphorylation of the oestrogen receptor alpha at serine 305 and prediction of tamoxifen resistance in breast cancer
- 2009
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Ingår i: JOURNAL OF PATHOLOGY. - : Wiley. - 0022-3417 .- 1096-9896. ; 217:3, s. 372-379
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Tidskriftsartikel (refereegranskat)abstract
- Phosphorylation of oestrogen receptor a at serine 305 (ER alpha S305-P) induces tamoxifen resistance in experimental studies, but does not influence response to other endocrine agents, such as fulvestrant. We evaluated ER alpha S305-P using immunohistochemistry in 377 breast carcinomas from premenopausal participants of a randomized trial (n = 248) and patients with advanced disease (n = 129). Among the premenopausal patients, adjuvant tamoxifen improved recurrence-free survival (RFS) for ER alpha S305-P-negative tumours (multivariate HR = 0.53, 95% CI 0.32-0.86, p = 0.010), but not for ER alpha S305-P-positive tumours (multivariate HR = 1.01, 95% CI 0.33-3.05, p = 0.99) (interaction p = 0.131). Notably, ER alpha S305-P was not significantly associated with RFS in patients not treated with tamoxifen (multivariate HR = 0.64, 95% CI 0.30-1.37, p = 0.248), indicating that ER alpha S305-P is a marker for treatment outcome rather than tumour progression. Given the direct experimental link between ER alpha S305-P and tamoxifen resistance and these first clinical data suggesting that premenopausal patients with ER alpha S305-P-positive breast cancer are resistant to adjuvant tamoxifen, further research is encouraged to study whether alternative endocrine treatment should be considered for this subgroup.
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| 9. |
- Kok, Marleen, et al.
(författare)
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Estrogen receptor-alpha phosphorylation at serine-118 and tamoxifen response in breast cancer.
- 2009
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 101:24, s. 1725-9
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Tidskriftsartikel (refereegranskat)abstract
- Although estrogen receptor-alpha (ER) [corrected] is a marker used to identify breast cancer patients most likely to benefit from endocrine therapy, approximately 50% of ER-positive [corrected] breast carcinomas are resistant to tamoxifen. Preclinical studies have shown that phosphorylation of ER [corrected] at serine-118 (ER alpha S118-P) is required for tamoxifen-mediated inhibition of ER-induced [corrected] gene expression. We evaluated the association between recurrence-free survival after tamoxifen treatment and ER alpha S118-P expression by use of Cox proportional hazards regression. Data were from 239 premenopausal patients with breast cancer who participated in a randomized trial of 2 years of adjuvant tamoxifen treatment vs no systemic treatment. ER alpha S118-P expression was assessed by immunohistochemistry and categorized by use of the Allred score (low expression = score of 0-6; high expression = score of 7-8). All statistical tests were two-sided. Compared with systemically untreated patients, we found evidence of a benefit from adjuvant tamoxifen among patients whose tumors had high ER alpha S118-P expression (23.7 recurrences per 1000 person-years versus 72.2 recurrences per 1000 person-years, hazard ratio [HR] of recurrence = 0.36, 95% confidence interval [CI] = 0.20 to 0.65) but not among patients whose tumors had low expression (51.0 recurrences per 1000 person-years versus 57.0 recurrences per 1000 person-years, HR of recurrence = 0.87, 95% CI = 0.51 to 1.48), a statistically significant difference (P for interaction = .037). ER alpha 118-P was not associated with recurrence-free survival among untreated patients. Thus, ER alpha S118-P expression appears to be associated with response to tamoxifen. [corrected]
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| 10. |
- Kok, Marleen, et al.
(författare)
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PKA-induced phosphorylation of ER alpha at serine 305 and high PAK1 levels is associated with sensitivity to tamoxifen in ER-positive breast cancer
- 2011
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Ingår i: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 1573-7217 .- 0167-6806. ; 125:1, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- Phosphorylation of estrogen receptor alpha at serine 305 (ER alpha S305-P) by protein kinase A (PKA) or p21-activated kinase 1 (PAK1) has experimentally been associated with tamoxifen sensitivity. Here, we investigated the clinical application of this knowledge to predict tamoxifen resistance in ER-positive breast cancer patients. Using immunohistochemistry, a score including PAK1 and co-expression of PKA and ER alpha S305-P (PKA/ER alpha S305-P) was developed on a training set consisting of 103 patients treated with tamoxifen for metastatic disease, and validated on 231 patients randomized between adjuvant tamoxifen or no treatment. In the training set, PAK1 levels were associated with tumor progression after tamoxifen (HR 1.57, 95% CI 0.99-2.48), as was co-expression of PKA and ER alpha S305-P (HR 2.00, 95% CI 1.14-3.52). In the validation set, a significant tamoxifen benefit was found among the 73% patients negative for PAK1 and PKA/ER alpha S305-P (HR 0.54, 95% CI 0.34-0.87), while others (27%) were likely to have no benefit from tamoxifen (HR 0.88, 95% 0.42-1.82). The test for interaction showed a significant difference in recurrence-free survival between groups defined by PAK1 and PKA/ER alpha S305-P (P = 0.037). Elevated PAK1 and PKA/ER alpha S305-P appeared to influence tamoxifen sensitivity. Both PAK1 and PKA/ER alpha S305-P levels were associated with sensitivity to tamoxifen in breast tumors and the combination of these variables should be considered in predicting tamoxifen benefit.
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