Upregulated SCUBE2 expression in breast cancer stem cells enhances triple negative breast cancer aggression through modulation of notch signaling and epithelial-to-mesenchymal transition.

Autor: Chen JH; Division of Medical Oncology and Hematology, Tri-Service General Hospital, National Defense Medical Centre, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan., Kuo KT; Division of Thoracic Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; Division of Thoracic Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan., Bamodu OA; Department of Hematology and Oncology, Cancer Center, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan; Department of Medical Research and Education, Taipei Medical University, Shuang Ho Hospital, New Taipei City, Taiwan., Lin YC; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan., Yang RB; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan., Yeh CT; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan; Department of Hematology and Oncology, Cancer Center, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan; Department of Medical Research and Education, Taipei Medical University, Shuang Ho Hospital, New Taipei City, Taiwan. Electronic address: ctyeh@s.tmu.edu.tw., Chao TY; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan; Department of Hematology and Oncology, Cancer Center, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan; Department of Medical Research and Education, Taipei Medical University, Shuang Ho Hospital, New Taipei City, Taiwan. Electronic address: 10575@s.tmu.edu.tw.
Jazyk: angličtina
Zdroj: Experimental cell research [Exp Cell Res] 2018 Sep 15; Vol. 370 (2), pp. 444-453. Date of Electronic Publication: 2018 Jul 05.
DOI: 10.1016/j.yexcr.2018.07.008
Abstrakt: Background: Metastatic and/or recurrent breast carcinomas are leading causes of cancer-related death worldwide. Breast cancer stem cells (BCSCs) have been implicated in cancer metastases and progression, thus, the need for the discovery and development of effective BCSCs-specific therapies against metastatic and triple negative breast cancer (TNBC). The expression of SCUBE2, originally identified in vascular endothelia, then in several non-endothelial cell types, is downregulated in invasive breast carcinomas. However, the role of SCUBE2 in BCSCs remains unknown. This present study investigated the probable involvements of SCUBE2 in BCSCs and TNBC metastasis.
Methods: The mRNA expression of SCUBE2, stemness and EMT markers in MDA-MB-231 and Hs578T tumorspheres or adherent cells were evaluated by qRT-PCR and microarray analyses. Using gene overexpression, in vitro migration and invasion assays, as well as in vivo bioluminescence imaging, we evaluated the role of SCUBE2 in MDA-MB-231 or Hs578T BCSCs. Western blot and cytotoxicity assays helped identify and validate SCUBE2 molecular target(s) and inhibitor(s).
Results: Concurrently increased SCUBE2 expression and cell motility were observed in TNBC tumorspheres compared to the parental adherent cells. SCUBE2 overexpression augmented BCSCs motility in vitro, and enhanced TNBC metastasis in vivo. While SCUBE2 overexpression activated Notch signaling its downregulation suppressed Notch signal effectors NICD, Jagged 1, HEY1, and HES1.
Conclusions: We demonstrate that SCUBE2 expression is upregulated in BCSCs, promote EMT and enhance TNBC metastasis by activating Notch signaling. This reveals a potential druggable molecular target and an effective therapeutic strategy against metastatic and aggressive TNBC.
(Copyright © 2018 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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