The Rab2A GTPase promotes breast cancer stem cells and tumorigenesis via Erk signaling activation.
Bottom Line: Mechanistically, Rab2A directly interacts with and prevents dephosphorylation/inactivation of Erk1/2 by the MKP3 phosphatase, resulting in Zeb1 upregulation and β-catenin nuclear translocation.Finally, Rab2A overexpression correlates with poor clinical outcome in breast cancer patients.Thus, Pin1/Rab2A/Erk drives BCSC expansion and tumorigenicity, suggesting potential drug targets.
Affiliation: Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.Show MeSH
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Mentions: We have previously demonstrated a fundamental role of Pin1 in regulating human BCSCs and mouse mammary stem cells (MaSCs) (Luo et al., 2014). To elucidate the underlying molecular mechanisms, we analyzed the effects of Pin1 knockout (KO) on gene expression in mouse mammary epithelial cells (MECs). Global expression profiling of Lin− MECs from Pin1 KO and wild-type (WT) littermates identified 1,723 genes that were downregulated in both Pin1 KO mice (Figures 1A and 1B; Tables S1 and S2). To narrow down the list of Pin1-regulated genes, we compared MEC gene expression with that of neurospheres prepared from the same mice (Figure 1B; Table S3). Although comparing expression profiles of stem cells from WT and Pin1 KO mice may be a better approach, the MaSC-enriched Lin−CD24+CD29+ or Lin−CD24medCD49fhi populations are very small in Pin1 KO mice (Luo et al., 2014), which made it difficult to get enough RNA from each mouse. As an alternative approach, we re-analyzed two published expression profiling datasets of mouse MaSCs and BCSCs (Stingl et al., 2006; Zhang et al., 2008) and compared them with our expression profiling of Lin− MECs and neurons from Pin1 KO and WT mice. We identified 14 genes downregulated in both Pin1 KO MECs and neurons and upregulated in either MaSCs or BCSCs (Figure 1C; Table S4).
Affiliation: Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.