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| 2. |
- Busch, Susann, et al.
(författare)
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Loss of TGF beta Receptor Type 2 Expression Impairs Estrogen Response and Confers Tamoxifen Resistance
- 2015
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Ingår i: Cancer Research. - : American Association for Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 75:7, s. 1457-1469
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Tidskriftsartikel (refereegranskat)abstract
- One third of the patients with estrogen receptor alpha (ER alpha)-positive breast cancer who are treated with the antiestrogen tamoxifen will either not respond to initial therapy or will develop drug resistance. Endocrine response involves crosstalk between ER alpha and TGF beta signaling, such that tamoxifen non-responsiveness or resistance in breast cancer might involve aberrant TGF beta signaling. In this study, we analyzed TGF beta receptor type 2 (TGFBR2) expression and correlated it with ER alpha status and phosphorylation in a cohort of 564 patients who had been randomized to tamoxifen or no-adjuvant treatment for invasive breast carcinoma. We also evaluated an additional four independent genetic datasets in invasive breast cancer. In all the cohorts we analyzed, we documented an association of low TGFBR2 protein and mRNA expression with tamoxifen resistance. Functional investigations confirmed that cell cycle or apoptosis responses to estrogen or tamoxifen in ER alpha-positive breast cancer cells were impaired by TGFBR2 silencing, as was ER alpha phosphorylation, tamoxifen-induced transcriptional activation of TGF beta, and upregulation of the multidrug resistance protein ABCG2. Acquisition of low TGFBR2 expression as a contributing factor to endocrine resistance was validated prospectively in a tamoxifen-resistant cell line generated by long-term drug treatment. Collectively, our results established a central contribution of TGF beta signaling in endocrine resistance in breast cancer and offered evidence that TGFBR2 can serve as an independent biomarker to predict treatment outcomes in ER alpha-positive forms of this disease. (C)2015 AACR.
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| 3. |
- Harrison, Hannah, et al.
(författare)
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Contrasting hypoxic effects on breast cancer stem cell hierarchy is dependent on ERα status.
- 2013
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Ingår i: Cancer research. - 1538-7445. ; 73:4, s. 1420-33
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Tidskriftsartikel (refereegranskat)abstract
- Tumor hypoxia is often linked to decreased survival in breast cancer patients and current therapeutic strategies aim to target the hypoxic response. One way in which this is done is by blocking hypoxia induced angiogenesis. Anti-angiogenic therapies show some therapeutic potential with increased disease free survival but these initial promising results are short lived and followed by tumor progression. We hypothesized that this may be due to altered cancer stem cell (CSC) activity resulting from increased tumor hypoxia. We studied the effects of hypoxia on CSC activity, using in vitro mammosphere and holoclone assays as well as in vivo limiting dilution experiments, in 13 patient-derived samples and 4 cell lines. There was a HIF1-alpha-dependent CSC increase in ER-alpha-positive cancers following hypoxic exposure which was blocked by inhibition of estrogen and Notch signaling. A contrasting decrease in CSC was seen in ER-alpha-negative cancers. We next developed a xenograft model of cell lines and patient-derived samples to assess the hypoxic-CSC response. Varying sizes of xenografts were collected and analyzed for HIF1-alpha expression and CSC. The same ER-alpha-dependent contrasting hypoxic-CSC response was seen validating the initial observation. These data suggest that ER-alpha-positive and negative breast cancer sub-types respond differently to hypoxia and, as a consequence, anti-angiogenic therapies will not be suitable for both subgroups.
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| 4. |
- Helczynska, Karolina, et al.
(författare)
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Hypoxia-inducible factor-2alpha correlates to distant recurrence and poor outcome in invasive breast cancer.
- 2008
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Ingår i: Cancer Research. - 1538-7445. ; 68:22, s. 9212-9220
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Tidskriftsartikel (refereegranskat)abstract
- Differential regulation as well as target gene specificity of the two hypoxia-inducible factor (HIF)-alpha subunits HIF-1alpha and HIF-2alpha in various tumors and cell lines have been suggested. In breast cancer, the prognostic significance of HIF-1alpha is not clear-cut and that of HIF-2alpha is largely unknown. Using IHC analyses of HIF-1alpha, HIF-2alpha, and vascular endothelial growth factor (VEGF) expression in a tissue microarray of invasive breast cancer specimens from 512 patients, we investigated the expression patterns of the 2 HIF-alpha subunits in relation to established clinicopathologic variables, VEGF expression, and survival. HIF-1alpha and HIF-2alpha protein levels and their effect on survival were additionally analyzed in a second cohort of 179 patients. To evaluate the individual role of each subunit in the hypoxic response and induction of VEGF, HIF-alpha protein and HIF-alpha and VEGF mRNA levels were further studied in cultured breast cancer cells after hypoxic induction and/or knockdown of HIF-alpha subunits by siRNA by Western blot and Quantitative Real-Time PCR techniques. We showed that although HIF-1alpha and HIF-2alpha protein levels in breast cancer specimens were not interrelated, high levels of both HIF-1alpha and HIF-2alpha associated to high VEGF expression. HIF-2alpha expression was an independent prognostic factor associated to reduced recurrence-free and breast cancer-specific survival, whereas HIF-1alpha did not exhibit these correlations. In cultured cells, acute hypoxia induced both HIF-proteins. At prolonged hypoxia, HIF-2alpha remained accumulated, whereas HIF-1alpha protein levels decreased, in agreement with the oxygen level and time-dependent induction of HIFs recently reported in neuroblastoma.
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| 6. |
- Jirström, Karin, et al.
(författare)
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Adverse effect of adjuvant tamoxifen in premenopausal breast cancer with cyclin D1 gene amplification
- 2005
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 65:17, s. 8009-8016
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Tidskriftsartikel (refereegranskat)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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| 7. |
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| 8. |
- Keune, Willem-Jan, et al.
(författare)
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Low PIP4K2B Expression in Human Breast Tumors Correlates with Reduced Patient Survival: A Role for PIP4K2B in the Regulation of E-Cadherin Expression
- 2013
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Ingår i: Cancer Research. - 1538-7445. ; 73:23, s. 6913-6925
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Tidskriftsartikel (refereegranskat)abstract
- Phosphatidylinositol-5-phosphate (PtdIns5P) 4-kinase beta (PIP4K2B) directly regulates the levels of two important phosphoinositide second messengers, PtdIns5P and phosphatidylinositol-(4,5)-bisphosphate [PtdIns(4,5)P-2]. PIP4K2B has been linked to the regulation of gene transcription, to TP53 and AKT activation, and to the regulation of cellular reactive oxygen accumulation. However, its role in human tumor development and on patient survival is not known. Here, we have interrogated the expression of PIP4K2B in a cohort (489) of patients with breast tumor using immunohistochemical staining and by a meta-analysis of gene expression profiles from 2,999 breast tumors, both with associated clinical outcome data. Low PIP4K2B expression was associated with increased tumor size, high Nottingham histological grade, Ki67 expression, and distant metastasis, whereas high PIP4K2B expression strongly associated with ERBB2 expression. Kaplan-Meier curves showed that both high and low PIP4K2B expression correlated with poorer patient survival compared with intermediate expression. In normal (MCF10A) and tumor (MCF7) breast epithelial cell lines, mimicking low PIP4K2B expression, using short hairpin RNA interference-mediated knockdown, led to a decrease in the transcription and expression of the tumor suppressor protein E-cadherin (CDH1). In MCF10A cells, knockdown of PIP4K2B enhanced TGF-beta-induced epithelial to mesenchymal transition (EMT), a process required during the development of metastasis. Analysis of gene expression datasets confirmed the association between low PIP4K2B and low CDH1expression. Decreased CDH1 expression and enhancement of TGF-beta-induced EMT by reduced PIP4K2B expression might, in part, explain the association between low PIP4K2B expression and poor patient survival. (C)2013 AACR.
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