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: To understand how Rab2A expands the BCSC-enriched population, we examined whether Rab2A activates Erk1/2, which is crucial for Ras to induce EMT and increase the CD24−CD44+ population (Shin et al., 2010). After serum starvation and EGF stimulation, Rab2A overexpression significantly increased Erk1/2 activation monitored by p-Erk1/2 in a time-dependent manner and also increased expression of Zeb1 (Figures 3A and 3B), a transcription factor critical for inducing the EMT and CD24−CD44+ population (Shin et al., 2010; Wellner et al., 2009). In contrast, Rab2A KD substantially impaired Erk1/2 activation (Figures 3A and 3B). We then asked whether the Q58H mutation might increase Erk1/2 phosphorylation. When expressed at the endogenous level, the Q58H mutant induced Erk1/2 activation even faster than WT Rab2A after EGF stimulation (Figures 3C and 3D). Thus, Rab2A and its Q58H mutant promote Erk1/2 activation. Next, we silenced Erk1 or 2 in Rab2A-overexpressing HMLE cells (Figure 3E). Erk1 KD only partially inhibited, but Erk2 KD substantially decreased, the ability of Rab2A overexpression to induce mammosphere formation (Figure 3F) and the CD24−CD44+ population (Figures 3G and 3H), indicating that Rab2A acts through Erk1/2 to maintain BCSC-associated properties.
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.