A Novel Oncogenic Role of Inositol Phosphatase SHIP2 in ER-Negative Breast Cancer Stem Cells: Involvement of JNK/Vimentin Activation. (15th July 2014)

• Record Type: Journal Article
• Authors: Fu, Chiung-Hui; Lin, Ruey-Jen; Yu, John; Chang, Wen-Wei; Liao, Guo-Shiou; Chang, Wen-Ying; Tseng, Ling-Ming; Tsai, Yi-Fang; Yu, Jyh-Cherng; Yu, Alice L.
• Is Part Of: Stem cells. Volume 32:Number 8(2014:Aug.)
• Page Start: 2048
• Page End: 2060
• Publication Date: 2014-07-15
• Subjects: SHIP2 -- Breast cancer stem cells -- JNK -- Vimentin; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.1735
• Languages: English
• ISSNs: 1066-5099

Abstract

Abstract: Overexpression of SH2-containing-5′-inositol phosphatase-2 (SHIP2) correlates with poor survival in breast cancer. However, its role in breast cancer stem cells (BCSCs) remains unclear. Here, we showed that the percentage of SHIP2 + cells was positively correlated with that of CD24 − CD44 + cells in 60 breast cancer specimens. Among 20 estrogen receptor (ER)-negative samples, 17 had greater SHIP2 expression in CD24 − CD44 + subpopulation than the remaining subpopulation. Data mining of microarray analysis of 295 breast tumors showed a significant correlation of higher SHIP2 expression with distant metastasis. Examination of patient-derived mouse xenografts revealed that SHIP2 protein and its tyrosine 1135 phosphorylation were significantly higher in BCSCs, identified as CD24 − CD44 + or aldehyde dehydrogenase (ALDH + ), than non-BCSCs. SHIP2 silencing or inhibitor of SHIP2 phosphatase significantly decreased mammosphere-forming efficiency, ALDH + subpopulation in vitro and tumorigenicity of BCSCs in vivo. Overexpression of SHIP2 enhanced the expression of epithelial–mesenchymal transition markers including vimentin (VIM), which was mainly expressed in ER-negative breast cancer cells with higher level in mammospheres than monolayer culture. Ablation of c-Jun N -terminal kinase 1 (JNK1), JNK2, or VIM diminished the increased ALDH + population and tumorigenicity, induced by SHIP2 overexpression. BCSCs displayed greater expression of phospho-JNK than non-BCSCs and silencing of JNK suppressed SHIP2-mediated upregulation of VIM. Furthermore, SHIP2 overexpression enhanced Akt activation, but Akt inhibition failed to influence SHIP2-induced phospho-JNK/VIM upregulation. In conclusion, SHIP2 plays a key role in BCSCs of ER-negative breast cancers through activation of Akt and JNK with upregulation of VIM and may serve as a target for therapy directed at BCSCs. Stem Cells 2014;32:2048–2060