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Sökning: WFRF:(Landberg G)

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31.
  • Simões, Bruno M, et al. (författare)
  • Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity.
  • 2015
  • Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 12:12, s. 1968-1977
  • Tidskriftsartikel (refereegranskat)abstract
    • Breast cancers (BCs) typically express estrogen receptors (ERs) but frequently exhibit de novo or acquired resistance to hormonal therapies. Here, we show that short-term treatment with the anti-estrogens tamoxifen or fulvestrant decrease cell proliferation but increase BC stem cell (BCSC) activity through JAG1-NOTCH4 receptor activation both in patient-derived samples and xenograft (PDX) tumors. In support of this mechanism, we demonstrate that high ALDH1 predicts resistance in women treated with tamoxifen and that a NOTCH4/HES/HEY gene signature predicts for a poor response/prognosis in 2 ER+ patient cohorts. Targeting of NOTCH4 reverses the increase in Notch and BCSC activity induced by anti-estrogens. Importantly, in PDX tumors with acquired tamoxifen resistance, NOTCH4 inhibition reduced BCSC activity. Thus, we establish that BCSC and NOTCH4 activities predict both de novo and acquired tamoxifen resistance and that combining endocrine therapy with targeting JAG1-NOTCH4 overcomes resistance in human breast cancers.
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32.
  • Skeie, G., et al. (författare)
  • Intake of whole grains and incidence of gastric and oesophageal cancer in the HELGA cohort
  • 2013
  • Ingår i: Annals of Nutrition and Metabolism. - : S. Karger. - 0250-6807 .- 1421-9697. ; 63:Supplement 1, s. 198-199
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Background and objectives: Whole grains are a good sourceof dietary fibre, but beneficial effects might also stem fromother components of the grain. Very few studies exist on intakeof whole grains and incidence of stomach and oesophagealcancer, but studies on dietary fibre and these cancers suggesta protective effect. The objective of this work was to study theassociation between intake of whole grains and incidence ofoesophageal and gastric cancer. Methods: The Helga cohort has 120 000 participants fromthe Norwegian Women and Cancer study, The Northern Sweden Health and Disease study and the Danish Diet, Cancerand Health study, recruited in 1992-1999. After exclusions, 112cases of oesophageal cancer, 185 cases of gastric cancer and 113700 other cohort members were included in the analyses. Theyprovided dietary information in semi-quantitative FFQs at baseline,and also information about other risk factors. Cancer information was obtained by linkage to the respective cancerregistries. The association between whole grain intake and cancerwas analysed with Cox proportional hazards models. Results: The median whole-grain intake was 47.4 g/day(5th-95th percentile: 13.3-101.1) in the non-cases, 37.5 g/day(10.8-87.2) in oesophageal cancer cases, and 45.1 g/day (8.1-99.1) in gastric cancer cases. A decreased risk of oesophagealcancer was observed, HR=0.83 (CI 0.69-0.99) p=0.04 per 20g of whole grains. The HR for highest compared with lowesttertile of intake was 0.56 (0.32-0.97) p=0.03. The analyses wereadjusted for country, smoking status, age at baseline, sex, processedmeat, alcohol and vitamin C. No association was foundfor whole grains and gastric cancer.Conclusion: In this study, higher intake of whole grains wasassociated with lower risk of oesophageal cancer. Acknowledgements: This work was supported by NordForsk– Centre of excellence programme HELGA (070015).
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33.
  • Tobin, N. P., et al. (författare)
  • An Endothelial Gene Signature Score Predicts Poor Outcome in Patients with Endocrine-Treated, Low Genomic Grade Breast Tumors
  • 2016
  • Ingår i: Clinical Cancer Research. - : American Association for Cancer Research (AACR). - 1078-0432 .- 1557-3265. ; 22:10, s. 2417-2426
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: The ability of vascular genes to provide treatment predictive information in breast cancer patients remains unclear. As such, we assessed the expression of genes representative of normal endothelial microvasculature (MV) in relation to treatment-specific patient subgroups. Experimental Design: We used expression data from 993 breast tumors to assess 57 MV genes (summarized to yield an MV score) as well as the genomic grade index (GGI) and PAM50 signatures. MV score was compared with CD31 staining by correlation and gene ontology (GO) analysis, along with clinicopathologic characteristics and PAM50 subtypes. Uni-, multivariate, and/or t-test analyses were performed in all and treatment-specific subgroups, along with a clinical trial cohort of patients with metastatic breast cancer, seven of whom received antiangiogenic therapy. Results: MV score did not correlate with microvessel density (correlation = 0.096), but displayed enrichment for angiogenic GO terms, and was lower in Luminal B tumors. In endocrine-treated patients, a high MV score was associated with decreased risk of metastasis [HR 0.58; 95% confidence interval (CI), 0.38-0.89], even after adjusting for histologic grade, but not GGI or PAM50. Subgroup analysis showed the prognostic strength of the MV score resided in low genomic grade tumors and MV score was significantly increased in metastatic breast tumors after treatment with sunitinib + docetaxel (P = 0.031). Conclusions: MV score identifies two groups of better and worse survival in low-risk endocrine-treated breast cancer patients. We also show normalization of tumor vasculature on a transcriptional level in response to an angiogenic inhibitor in human breast cancer samples. (C) 2016 AACR.
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34.
  • Williams, K. E., et al. (författare)
  • Focal Adhesion Kinase and Wnt Signaling Regulate Human Ductal Carcinoma In Situ Stem Cell Activity and Response to Radiotherapy
  • 2015
  • Ingår i: Stem Cells. - : Oxford University Press (OUP). - 1066-5099 .- 1549-4918. ; 33:2, s. 327-341
  • Tidskriftsartikel (refereegranskat)abstract
    • Cancer stem cells (CSCs) can avoid or efficiently repair DNA damage from radio and chemotherapy, which suggests they play a role in disease recurrence. Twenty percentage of patients treated with surgery and radiotherapy for ductal carcinoma in situ (DCIS) of the breast recur and our previous data show that high grade DCIS have increased numbers of CSCs. Here, we investigate the role of focal adhesion kinase (FAK) and Wnt pathways in DCIS stem cells and their capacity to survive irradiation. Using DCIS cell lines and patient samples, we demonstrate that CSC-enriched populations are relatively radioresistant and possess high FAK activity. Immunohistochemical studies of active FAK in DCIS tissue show high expression was associated with a shorter median time to recurrence. Treatment with a FAK inhibitor or FAK siRNA in nonadherent and three-dimensional matrigel culture reduced mammosphere formation, and potentiated the effect of 2 Gy irradiation. Moreover, inhibition of FAK in vitro and in vivo decreased self-renewal capacity, levels of Wnt3a and B-Catenin revealing a novel FAK-Wnt axis regulating DCIS stem cell activity. Overall, these data establish that the FAK-Wnt axis is a promising target to eradicate self-renewal capacity and progression of human breast cancers.
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35.
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