SNAI2 upregulation is associated with an aggressive phenotype in fulvestrant-resistant breast cancer cells and is an indicator of poor response to endocrine therapy in estrogen receptor-positive metastatic breast cancer.
Background: Endocrine resistance in estrogen receptor-positive (ER+) breast cancer is a major clinical problem and is associated with accelerated cancer cell growth, increased motility and acquisition of mesenchymal characteristics. However, the specific molecules and pathways involved in these alte...
| Publicado en: | Breast Cancer Research Vol. 20; no. 1 |
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| Autores principales: | , , , , |
| Formato: | research Journal Article |
| Publicado: |
BioMed Central
6/19/2018
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=130279857&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 130279857 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 14655411 8UYJ jtl: Breast Cancer Research issn: 14655411 maglogo: N pubinfo: dt: 6/19/2018 vid: 20 iid: 1 pid: 24147 pub: BioMed Central artinfo: ui: 130279857 130279857 NLM29921289 130279857 10.1186/s13058-018-0988-9 NLM29921289 130279857 ppct: 1 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: SNAI2 upregulation is associated with an aggressive phenotype in fulvestrant-resistant breast cancer cells and is an indicator of poor response to endocrine therapy in estrogen receptor-positive metastatic breast cancer. aug: au: Alves, Carla L. Elias, Daniel Lyng, Maria B. Bak, Martin Ditzel, Henrik J. affil: Department of Cancer and Inflammation Research, Institute of Molecular Medicine University of Southern Denmark J.B. Winsløwsvej 25 5000 Odense C Denmark sug: subj: Breast Neoplasms Drug Therapy Antineoplastic Agents, Hormonal Administration and Dosage Drug Resistance, Neoplasm Cell Physiology Drug Effects Genes Aged Breast Neoplasms Adult Antineoplastic Agents, Hormonal Adverse Effects Human Cell Line, Tumor Breast Neoplasms Pathology Proteins Neoplasm Metastasis Female Middle Age Validation Studies Comparative Studies Evaluation Research Multicenter Studies Aged: 65+ years Adult: 19-44 years Middle Aged: 45-64 years Female ab: Background: Endocrine resistance in estrogen receptor-positive (ER+) breast cancer is a major clinical problem and is associated with accelerated cancer cell growth, increased motility and acquisition of mesenchymal characteristics. However, the specific molecules and pathways involved in these altered features remain to be detailed, and may be promising therapeutic targets to overcome endocrine resistance.Methods: In the present study, we evaluated altered expression of epithelial-mesenchymal transition (EMT) regulators in ER+ breast cancer cell models of tamoxifen or fulvestrant resistance, by gene expression profiling. We investigated the specific role of increased SNAI2 expression in fulvestrant-resistant cells by gene knockdown and treatment with a SNAIL-p53 binding inhibitor, and evaluated the effect on cell growth, migration and expression of EMT markers. Furthermore, we evaluated SNAI2 expression by immunohistochemical analysis in metastatic samples from two cohorts of patients with breast cancer treated with endocrine therapy in the advanced setting.Results: SNAI2 was found to be significantly upregulated in all endocrine-resistant cells compared to parental cell lines, while no changes were observed in the expression of other EMT-associated transcription factors. SNAI2 knockdown with specific small interfering RNA (siRNA) converted the mesenchymal-like fulvestrant-resistant cells into an epithelial-like phenotype and reduced cell motility. Furthermore, inhibition of SNAI2 with specific siRNA or a SNAIL-p53 binding inhibitor reduced growth of cells resistant to fulvestrant treatment. Clinical evaluation of SNAI2 expression in two independent cohorts of patients with ER+ metastatic breast cancer treated with endocrine therapy in the advanced setting (N = 86 and N = 67) showed that high SNAI2 expression in the metastasis correlated significantly with shorter progression-free survival on endocrine treatment (p = 0.0003 and p = 0.004).Conclusions: Our results suggest that SNAI2 is a key regulator of the aggressive phenotype observed in endocrine-resistant breast cancer cells, an independent prognostic biomarker in ER+ advanced breast cancer treated with endocrine therapy, and may be a promising therapeutic target in combination with endocrine therapies in ER+ metastatic breast cancer exhibiting high SNAI2 levels. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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