title: The Rab2A GTPase promotes breast cancer stem cells and tumorigenesis via Erk signaling activation.
abstract: Proline-directed phosphorylation is regulated by the prolyl isomerase Pin1, which plays a fundamental role in driving breast cancer stem-like cells (BCSCs). Rab2A is a small GTPase critical for vesicle trafficking. Here, we show that Pin1 increases Rab2A transcription to promote BCSC expansion and tumorigenesis in vitro and in vivo. 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. In cancer cells, Rab2A is activated via gene amplification, mutation or Pin1 overexpression. Rab2A overexpression or mutation endows BCSC traits to primary normal human breast epithelial cells, whereas silencing Rab2A potently inhibits the expansion and tumorigenesis of freshly isolated BCSCs. 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.
authors.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.
authors.forename: Man-Li
authors.initials: ML
authors.lastname: Luo
authors.affiliation: Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Gong
authors.affiliation: Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Chun-Hau
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Pengyu
authors.initials: P
authors.lastname: Huang
authors.affiliation: Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Institute for Translational Medicine, Fujian Medical University, Fuzhou 350108, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zheng
authors.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.
authors.forename: Yandan
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Shuo
authors.initials: S
authors.lastname: Wei
authors.affiliation: Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Gerburg
authors.initials: G
authors.lastname: Wulf
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Judy
authors.initials: J
authors.lastname: Lieberman
authors.affiliation: Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Xiao Zhen
authors.initials: XZ
authors.lastname: Zhou
authors.affiliation: Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
authors.forename: Erwei
authors.initials: E
authors.lastname: Song
authors.affiliation: Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Institute for Translational Medicine, Fujian Medical University, Fuzhou 350108, China. Electronic address: klu@bidmc.harvard.edu.
authors.forename: Kun Ping
authors.initials: KP
authors.lastname: Lu
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics*; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D019696:Peptidylprolyl Isomerase / Q000096:biosynthesis* / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D020691:rab GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D020691:rab GTP-Binding Proteins; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase
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