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Estrogen Receptor β as a Therapeutic Target in Breast Cancer Stem Cells.
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2017 (English)In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 109, no 3, p. 1-14Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Oxford University Press, 2017. Vol. 109, no 3, p. 1-14
Keywords [en]
stem cells, estrogen, breast cancer
National Category
Cell Biology
Identifiers
URN: urn:nbn:se:kth:diva-206374DOI: 10.1093/jnci/djw236ISI: 000396773900013PubMedID: 28376210Scopus ID: 2-s2.0-85018184387OAI: oai:DiVA.org:kth-206374DiVA, id: diva2:1092202
Funder
VINNOVA, GROWTH 291795Swedish Cancer Society, CAN 2015/591King Gustaf V Jubilee Fund
Note

QC 20170503

Available from: 2017-05-02 Created: 2017-05-02 Last updated: 2017-10-30Bibliographically approved

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