The forkhead transcription factor FOXM1 promotes endocrine resistance and invasiveness in estrogen receptor-positive breast cancer by expansion of stem-like cancer cells.
Introduction: The forkhead transcription factor FOXM1 coordinates expression of cell cycle-related genes and plays a pivotal role in tumorigenesis and cancer progression. We previously showed that FOXM1 acts downstream of 14-3-3ζ signaling, the elevation of which correlates with a more aggressive tu...
| Published in: | Breast Cancer Research Vol. 16; no. 4; pp. 436 - 437 |
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| Main Authors: | , , , , , |
| Format: | research Journal Article |
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BioMed Central
2014
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| Online Access: | View this record in EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=109773035&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 109773035 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 14655411 8UYJ jtl: Breast Cancer Research issn: 14655411 maglogo: N pubinfo: dt: 2014 vid: 16 iid: 4 pid: 24147 pub: BioMed Central artinfo: ui: 109773035 109773035 NLM25213081 2012868087 10.1186/s13058-014-0436-4 NLM25213081 PMC4303117 109773035 ppf: 436 ppct: 1 formats: fmt: @attributes: type: P tig: atl: The forkhead transcription factor FOXM1 promotes endocrine resistance and invasiveness in estrogen receptor-positive breast cancer by expansion of stem-like cancer cells. aug: au: Bergamaschi, Anna Madak-Erdogan, Zeynep Kim, Yu Jin Choi, Yoon-La Lu, Hailing Katzenellenbogen, Benita S sug: subj: Breast Neoplasms Metabolism Drug Resistance, Neoplasm Proteins Physiology Stem Cells Physiology Proteins Metabolism Antineoplastic Agents, Hormonal Pharmacodynamics Antineoplastic Agents, Hormonal Therapeutic Use Breast Neoplasms Drug Therapy Breast Neoplasms Mortality Breast Neoplasms Pathology Cell Physiology Female Genetic Research Human Kaplan-Meier Estimator Cell Line, Tumor Neoplasm Invasiveness Tamoxifen Pharmacodynamics Tamoxifen Therapeutic Use Treatment Outcomes Female ab: Introduction: The forkhead transcription factor FOXM1 coordinates expression of cell cycle-related genes and plays a pivotal role in tumorigenesis and cancer progression. We previously showed that FOXM1 acts downstream of 14-3-3ζ signaling, the elevation of which correlates with a more aggressive tumor phenotype. However, the role that FOXM1 might play in engendering resistance to endocrine treatments in estrogen receptor-positive (ER+) patients when tumor FOXM1 is high has not been clearly defined yet.Methods: We analyzed FOXM1 protein expression by immunohistochemistry in 501 ER-positive breast cancers. We also mapped genome-wide FOXM1, extracellular signal-regulated kinase 2 and ERα binding events by chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) in hormone-sensitive and resistant breast cancer cells after tamoxifen treatment. These binding profiles were integrated with gene expression data derived from cells before and after FOXM1 knockdown to highlight specific FOXM1 transcriptional networks. We also modulated the levels of FOXM1 and newly discovered FOXM1-regulated genes and examined their impact on the cancer stem-like cell population and on cell invasiveness and resistance to endocrine treatments.Results: FOXM1 protein expression was high in 20% of the tumors, which correlated with significantly reduced survival in these patients (P = 0.003 by logrank Mantel-Cox test). ChIP-seq analyses revealed that FOXM1 binding sites were enriched at the transcription start site of genes involved in cell-cycle progression, maintenance of stem cell properties, and invasion and metastasis, all of which are associated with a poor prognosis in ERα-positive patients treated with tamoxifen. Integration of binding profiles with gene expression highlighted FOXM1 transcriptional networks controlling cell proliferation, stem cell properties, invasion and metastasis. Increased expression of FOXM1 was associated with an expansion of the cancer stem-like cell population and with increased cell invasiveness and resistance to endocrine treatments. Use of a selective FOXM1 inhibitor proved very effective in restoring endocrine therapy sensitivity and decreasing breast cancer aggressiveness.Conclusions: Collectively, our findings uncover novel roles for FOXM1 and FOXM1-regulated genes in promoting cancer stem-like cell properties and therapy resistance. They highlight the relevance of FOXM1 as a therapeutic target to be considered for reducing invasiveness and enhancing breast cancer response to endocrine treatments. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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