A Novel Oncogenic Role of Inositol Phosphatase SHIP2 in ER-Negative Breast Cancer Stem Cells: Involvement of JNK/Vimentin Activation

Abstract

Overexpression of SH2-containing-5 0 -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 1 cells was positively correlated with that of CD24 2 CD44 1 cells in 60 breast cancer specimens. Among 20 estrogen receptor (ER)-negative samples, 17 had greater SHIP2 expression in CD24 2 CD44 1 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 2 CD44 1 or aldehyde dehydrogenase (ALDH 1 ), than non-BCSCs. SHIP2 silencing or inhibitor of SHIP2 phosphatase significantly decreased mammosphere-forming efficiency, ALDH 1 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 1 population and tumorigenicity, induced by SHIP2 overexpression. BCSCs displayed greater expression of phospho-JNK than nonBCSCs 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 ERnegative breast cancers through activation of Akt and JNK with upregulation of VIM and may serve as a target for therapy directed at BCSCs.

Lipid phosphatase SHIP2 functions as oncogene in colorectal cancer by regulating PKB activation

“…Together, these data suggest that SHIP2 increases the oncogenic potential of colonic epithelial cells. This fits well with previous reports, showing that SHIP2 expression is increased in breast cancer samples [29, 30] and that treatment of breast cancer cell lines with SHIP2 inhibitors results in cell death [13]. Other studies have also confirmed overexpression of SHIP2 in CRC, laryngeal squamous cell carcinoma and non-small lung cell cancer [31–33].…”

Suppression of SHIP2 contributes to tumorigenesis and proliferation of gastric cancer cells via activation of Akt

“…However, SHIP2 has contrasting effect on Akt activation in different cancer cell types. Prasad et al established that SHIP2 promoted cell migration in breast cancer via EGFR-induced Akt activation [12,13]. These reports, taken in conjunction with our findings, suggest that the pro-or anti-tumorigenic effect of SHIP2 largely depends on cell context.…”

“…SHIP2 has been demonstrated to promote breast cancer cell proliferation and tumor metastasis by interacting with c-cbl to prevent epidermal growth factor receptor (EGFR) turnover, enhancing EGF-induced Akt activation [10,11]. In ER-negative breast cancer stem cells, SHIP2 activates Akt and JNK and upregulates the epithelial-mesenchymal transition marker vimentin [12]. In contrast, in squamous cell carcinoma epithelial cells, miRNA-205 targets SHIP2, thereby enhancing Akt phosphorylation and inhibiting apoptosis [13].…”

Enrichment of Human Stem-Like Prostate Cells with s-SHIP Promoter Activity Uncovers a Role in Stemness for the Long Noncoding RNA H19

“…Even though this protein lacks the SH2 domain as compared with SHIP1, s-SHIP contains cell signaling domains, including the 5¢-inositol phosphatase domain [16], which might play a key role in controlling phosphatidylinositol-3-kinase (PI3K)/AKT activation. From this point of view, an interesting study has recently demonstrated the importance of the enzymatic activity of SHIP2, another 5¢-inositol phosphatase, for breast cancer stem cells [34]. Altogether, these studies support the idea that s-SHIP promoter expression offers a valuable and unique marker of mammary and prostate stem cell populations that could lead to the identification of molecules involved in stem cell biology.…”