Dataset Information
Estrogen Receptor ? as a Therapeutic Target in Breast Cancer Stem Cells.
Ontology highlight
ABSTRACT: 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 ER?-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 ER? but upregulation of ER? in BSCs associated with phenotypic stem cell markers and responsible for the proliferative role of estrogens. Knockdown of ER? 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 ER?-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 ER? (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 ER? as a mediator of estrogen action in BSCs and a novel target for endocrine therapy.
SUBMITTER: Ma R
PROVIDER: S-EPMC5441302 | biostudies-literature | 2017 Mar
REPOSITORIES: biostudies-literature
Publications
Estrogen Receptor β as a Therapeutic Target in Breast Cancer Stem Cells.
Journal of the National Cancer Institute 20170301 3
<h4>Background</h4>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.<h4>Methods</h4>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 ...[more]
