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

Jia Hong Chen, Kuang Tai Kuo, Oluwaseun Adebayo Bamodu, Yuh Charn Lin, Ruey Bing Yang, Chi Tai Yeh, Tsu Yi Chao

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish
JournalExperimental Cell Research
DOIs
Publication statusAccepted/In press - Jan 1 2018

Fingerprint

Triple Negative Breast Neoplasms
Epithelial-Mesenchymal Transition
Neoplastic Stem Cells
Aggression
Breast Neoplasms
Neoplasm Metastasis
Cell Movement
Down-Regulation
Vascular Endothelium
Microarray Analysis
Cell- and Tissue-Based Therapy
Neoplasms
Western Blotting

Keywords

  • Breast cancer stem cells
  • Metastasis
  • Notch signaling
  • SCUBE2
  • TNBC

ASJC Scopus subject areas

  • Cell Biology

Cite this

Upregulated SCUBE2 expression in breast cancer stem cells enhances triple negative breast cancer aggression through modulation of notch signaling and epithelial-to-mesenchymal transition. / Chen, Jia Hong; Kuo, Kuang Tai; Bamodu, Oluwaseun Adebayo; Lin, Yuh Charn; Yang, Ruey Bing; Yeh, Chi Tai; Chao, Tsu Yi.

In: Experimental Cell Research, 01.01.2018.

Research output: Contribution to journalArticle

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title = "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.",
keywords = "Breast cancer stem cells, Metastasis, Notch signaling, SCUBE2, TNBC",
author = "Chen, {Jia Hong} and Kuo, {Kuang Tai} and Bamodu, {Oluwaseun Adebayo} and Lin, {Yuh Charn} and Yang, {Ruey Bing} and Yeh, {Chi Tai} and Chao, {Tsu Yi}",
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T1 - Upregulated SCUBE2 expression in breast cancer stem cells enhances triple negative breast cancer aggression through modulation of notch signaling and epithelial-to-mesenchymal transition

AU - Chen, Jia Hong

AU - Kuo, Kuang Tai

AU - Bamodu, Oluwaseun Adebayo

AU - Lin, Yuh Charn

AU - Yang, Ruey Bing

AU - Yeh, Chi Tai

AU - Chao, Tsu Yi

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - Breast cancer stem cells

KW - Metastasis

KW - Notch signaling

KW - SCUBE2

KW - TNBC

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