Gain of HIF1 Activity and Loss of miRNA let-7d Promote Breast Cancer Metastasis to the Brain via the PDGF/PDGFR Axis.

Autor: Wyss CB; Experimental and Translational Oncology, Pathology, Department of Oncology Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland., Duffey N; Experimental and Translational Oncology, Pathology, Department of Oncology Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland., Peyvandi S; Experimental and Translational Oncology, Pathology, Department of Oncology Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland., Barras D; Bioinformatics Core Facility, Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland., Martinez Usatorre A; Department of Oncology, Centre Hospitalier Universitaire Vaudois, Ludwig Center for Cancer Research, University of Lausanne, Lausanne, Switzerland., Coquoz O; Experimental and Translational Oncology, Pathology, Department of Oncology Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland., Romero P; Department of Oncology, Centre Hospitalier Universitaire Vaudois, Ludwig Center for Cancer Research, University of Lausanne, Lausanne, Switzerland., Delorenzi M; Bioinformatics Core Facility, Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.; Department of Oncology, Centre Hospitalier Universitaire Vaudois, Ludwig Center for Cancer Research, University of Lausanne, Lausanne, Switzerland., Lorusso G; Experimental and Translational Oncology, Pathology, Department of Oncology Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland. curzio.ruegg@unifr.ch girieca.lorusso@gmail.com., Rüegg C; Experimental and Translational Oncology, Pathology, Department of Oncology Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland. curzio.ruegg@unifr.ch girieca.lorusso@gmail.com.
Jazyk: angličtina
Zdroj: Cancer research [Cancer Res] 2021 Feb 01; Vol. 81 (3), pp. 594-605.
DOI: 10.1158/0008-5472.CAN-19-3560
Abstrakt: Early detection and adjuvant therapies have significantly improved survival of patients with breast cancer over the past three decades. In contrast, management of metastatic disease remains unresolved. Brain metastasis is a late complication frequently observed among patients with metastatic breast cancer, whose poor prognosis calls for novel and more effective therapies. Here, we report that active hypoxia inducible factor-1 (HIF1) signaling and loss of the miRNA let-7d concur to promote brain metastasis in a recently established model of spontaneous breast cancer metastasis from the primary site to the brain (4T1-BM 2 ), and additionally in murine and human experimental models of breast cancer brain metastasis (D2A1-BM 2 and MDA231-BrM 2 ). Active HIF1 and let-7d loss upregulated expression of platelet-derived growth factor (PDGF) B/A in murine and human brain metastatic cells, respectively, while either individual silencing of HIF1α and PDGF-A/B or let-7d overexpression suppressed brain metastasis formation in the tested models. Let-7d silencing upregulated HIF1α expression and HIF1 activity, indicating a regulatory hierarchy of the system. The clinical relevance of the identified targets was supported by human gene expression data analyses. Treatment of mice with nilotinib, a kinase inhibitor impinging on PDGF receptor (PDGFR) signaling, prevented formation of spontaneous brain metastases in the 4T1-BM 2 model and reduced growth of established brain metastases in mouse and human models. These results identify active HIF1 signaling and let-7d loss as coordinated events promoting breast cancer brain metastasis through increased expression of PDGF-A/B. Moreover, they identify PDGFR inhibition as a potentially actionable therapeutic strategy for patients with brain metastatis. SIGNIFICANCE: These findings show that loss of miRNA let-7d and active HIF1 signaling promotes breast cancer brain metastasis via PDGF and that pharmacologic inhibition of PDGFR suppresses brain metastasis, suggesting novel therapeutic opportunities. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/3/594/F1.large.jpg. See related article by Thies et al., p. 606 .
(©2021 American Association for Cancer Research.)
Databáze: MEDLINE
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