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.
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.
Exp Cell Res. 2018 Sep 15;370(2):444-453. doi: 10.1016/j.yexcr.2018.07.008. Epub 2018 Jul 5.
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.
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).
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.
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.
转移性和/或复发性乳腺癌是全球癌症相关死亡的主要原因。乳腺癌干细胞（BCSCs）与癌症转移和进展有关，因此需要发现和开发针对转移性和三阴性乳腺癌（TNBC）的有效 BCSCs 特异性疗法。SCUBE2 的表达最初在血管内皮细胞中被鉴定出来，然后在几种非内皮细胞类型中被下调，在侵袭性乳腺癌中被下调。然而，SCUBE2 在 BCSCs 中的作用尚不清楚。本研究探讨了 SCUBE2 在 BCSCs 和 TNBC 转移中的可能作用。
通过 qRT-PCR 和微阵列分析评估 MDA-MB-231 和 Hs578T 肿瘤球或贴壁细胞中 SCUBE2、干性和 EMT 标志物的 mRNA 表达。通过基因过表达、体外迁移和侵袭测定以及体内生物发光成像，我们评估了 SCUBE2 在 MDA-MB-231 或 Hs578T BCSCs 中的作用。Western blot 和细胞毒性测定有助于确定和验证 SCUBE2 的分子靶标和抑制剂。
与亲本贴壁细胞相比，TNBC 肿瘤球中同时观察到 SCUBE2 表达增加和细胞迁移增加。SCUBE2 过表达增强了 BCSCs 的体外迁移能力，并增强了 TNBC 的体内转移。虽然 SCUBE2 过表达激活了 Notch 信号，但它下调了 Notch 信号效应子 NICD、Jagged 1、HEY1 和 HES1。
我们证明 SCUBE2 的表达在 BCSCs 中上调，通过激活 Notch 信号促进 EMT 并增强 TNBC 转移。这揭示了一个潜在的可靶向分子靶标和针对转移性和侵袭性 TNBC 的有效治疗策略。
