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  • Ma, RanKarolinska Institutet,Karolinska Institute, Sweden (author)

Estrogen Receptor β as a Therapeutic Target in Breast Cancer Stem Cells.

  • Article/chapterEnglish2017

Publisher, publication year, extent ...

  • 2017-02-10
  • Oxford University Press,2017
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:kth-206374
  • https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-206374URI
  • https://doi.org/10.1093/jnci/djw236DOI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:135261010URI
  • https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-136043URI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • QC 20170503
  • Funding Agencies|Swedish Society of Medicine; Swedish Society for Medical Research (SSMF); Magnus Bergvalls Stiftelse; Karolinska Institutes Theme Center in Breast Cancer (BRECT); Linnecenter for Prevention of Breast and Prostate cancer (CRisP); Swedish Cancer Society; Stockholm Cancer Society; King Gustav V Jubilee Fund; Karolinska Institutet; Stockholm County Council Research Strategy Committee; Swedish Breast Cancer Association; Science for Life-Astra Zeneca; Marie Curie Actions via the VINNOVA program Mobility for Growth [291795]
  • Background: Breast cancer cells with tumor-initiating capabilities (BSCs) are considered to maintain tumor growth and govern metastasis. Hence, targeting BSCs will be crucial to achieve successful treatment of breast cancer.Methods: We characterized mammospheres derived from more than 40 cancer patients and two breast cancer cell lines for the expression of estrogen receptors (ERs) and stem cell markers. Mammosphere formation and proliferation assays were performed on cells from 19 cancer patients and five healthy individuals after incubation with ER-subtype selective ligands. Transcriptional analysis was performed to identify pathways activated in ERβ-stimulated mammospheres and verified using in vitro experiments. Xenograft models (n = 4 or 5 per group) were used to study the role of ERs during tumorigenesis.Results: We identified an absence of ERα but upregulation of ERβ in BSCs associated with phenotypic stem cell markers and responsible for the proliferative role of estrogens. Knockdown of ERβ caused a reduction of mammosphere formation in cell lines and in patient-derived cancer cells (40.7%, 26.8%, and 39.1%, respectively). Gene set enrichment analysis identified glycolysis-related pathways (false discovery rate < 0.001) upregulated in ERβ-activated mammospheres. We observed that tamoxifen or fulvestrant alone was insufficient to block proliferation of patient-derived BSCs while this could be accomplished by a selective inhibitor of ERβ (PHTPP; 53.7% in luminal and 45.5% in triple-negative breast cancers). Furthermore, PHTPP reduced tumor initiation in two patient-derived xenografts (75.9% and 59.1% reduction in tumor volume, respectively) and potentiated tamoxifen-mediated inhibition of tumor growth in MCF7 xenografts.Conclusion: We identify ERβ as a mediator of estrogen action in BSCs and a novel target for endocrine therapy.

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  • Karthik, Govindasamy-MuralidharanKarolinska Institutet,Karolinska Institute, Sweden (author)
  • Lövrot, JohnKarolinska Institutet,Karolinska Institute, Sweden (author)
  • Haglund, FelixKarolinska Institutet,Karolinska Institute, Sweden; Karolinska University of Lab, Sweden (author)
  • Rosin, GustafKarolinska Institute, Sweden (author)
  • Katchy, AnneUniversity of Houston, TX USA (author)
  • Zhang, XiaonanKarolinska Institutet,Karolinska Institute, Sweden (author)
  • Viberg, LisaKarolinska Institute, Sweden (author)
  • Frisell, JanKarolinska Institutet,Karolinska University Hospital, Sweden (author)
  • Williams, Cecilia,1969-Karolinska Institutet,KTH,Proteomik och nanobioteknologi,Karolinska Inst, Dept Biosci & Nutr, Huddinge, Sweden; Univ Houston, Dept Biol & Biochem, Ctr Nucl Receptors & Cell Signaling, Houston, TX USA,Cecilia Williams,Karolinska Institute, Sweden; University of Houston, TX USA; Royal Institute Technology, Sweden(Swepub:kth)u1ygqmuy (author)
  • Linder, StigLinköpings universitet,Karolinska Institutet,Avdelningen för läkemedelsforskning,Medicinska fakulteten,Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden(Swepub:liu)stili13 (author)
  • Fredriksson, IrmaKarolinska Institutet,Karolinska Institute, Sweden; Karolinska University Hospital, Sweden (author)
  • Hartman, JohanKarolinska Institutet,Karolinska Institute, Sweden; Karolinska University of Lab, Sweden (author)
  • Karolinska InstitutetKarolinska Institute, Sweden (creator_code:org_t)

Related titles

  • In:Journal of the National Cancer Institute: Oxford University Press109:3, s. 1-140027-88741460-2105

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