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

Abstract：

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.

journal_name

Exp Cell Res

journal_title

Experimental cell research

authors

Chen JH,Kuo KT,Bamodu OA,Lin YC,Yang RB,Yeh CT,Chao TY

doi

10.1016/j.yexcr.2018.07.008

subject

Has Abstract

pub_date

2018-09-15 00:00:00

pages

444-453

issue

eissn

0014-4827

issn

1090-2422

pii

S0014-4827(18)30398-7

journal_volume

370

pub_type

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