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

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

Ma, Ran (author): Karolinska Institutet,Karolinska Institute, Sweden

Karthik, Govindasamy-Muralidharan (author): Karolinska Institutet,Karolinska Institute, Sweden

Lövrot, John (author): Karolinska Institutet,Karolinska Institute, Sweden

Haglund, Felix (author): Karolinska Institutet,Karolinska Institute, Sweden; Karolinska University of Lab, Sweden

Rosin, Gustaf (author): Karolinska Institute, Sweden

Katchy, Anne (author): University of Houston, TX USA

Zhang, Xiaonan (author): Karolinska Institutet,Karolinska Institute, Sweden

Viberg, Lisa (author): Karolinska Institute, Sweden

Frisell, Jan (author): Karolinska Institutet,Karolinska University Hospital, Sweden

Williams, Cecilia, 1969- (author): 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

Linder, Stig (author): Linköpings universitet,Karolinska Institutet,Avdelningen för läkemedelsforskning,Medicinska fakulteten,Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden

Fredriksson, Irma (author): Karolinska Institutet,Karolinska Institute, Sweden; Karolinska University Hospital, Sweden

Hartman, Johan (author): Karolinska Institutet,Karolinska Institute, Sweden; Karolinska University of Lab, Sweden

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2017-02-10
2017
English.
In: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 109:3, s. 1-14

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Journal article (peer-reviewed)

Abstract Subject headings

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.

Subject headings

NATURVETENSKAP -- Biologi -- Cellbiologi (hsv//swe)
NATURAL SCIENCES -- Biological Sciences -- Cell Biology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

Keyword

stem cells
estrogen
breast cancer

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By the author/editor: Ma, Ran; Karthik, Govinda ...; Lövrot, John; Haglund, Felix; Rosin, Gustaf; Katchy, Anne; show more...; Zhang, Xiaonan; Viberg, Lisa; Frisell, Jan; Williams, Cecili ...; Linder, Stig; Fredriksson, Irm ...; Hartman, Johan; show less...

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NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Cell Biology

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Cancer and Oncol ...

Articles in the publication: Journal of the N ...

By the university: Royal Institute of Technology; Karolinska Institutet; Linköping University

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