title: G Protein-coupled Receptor Kinase 2 (GRK2) Promotes Breast Tumorigenesis Through a HDAC6-Pin1 Axis.
abstract: In addition to oncogenic drivers, signaling nodes can critically modulate cancer-related cellular networks to strength tumor hallmarks. We identify G-protein-coupled receptor kinase 2 (GRK2) as a relevant player in breast cancer. GRK2 is up-regulated in breast cancer cell lines, in spontaneous tumors in mice, and in a proportion of invasive ductal carcinoma patients. Increased GRK2 functionality promotes the phosphorylation and activation of the Histone Deacetylase 6 (HDAC6) leading to de-acetylation of the Prolyl Isomerase Pin1, a central modulator of tumor progression, thereby enhancing its stability and functional interaction with key mitotic regulators. Interestingly, a correlation between GRK2 expression and Pin1 levels and de-acetylation status is detected in breast cancer patients. Activation of the HDAC6-Pin1 axis underlies the positive effects of GRK2 on promoting growth factor signaling, cellular proliferation and anchorage-independent growth in both luminal and basal breast cancer cells. Enhanced GRK2 levels promote tumor growth in mice, whereas GRK2 down-modulation sensitizes cells to therapeutic drugs and abrogates tumor formation. Our data suggest that GRK2 acts as an important onco-modulator by strengthening the functionality of key players in breast tumorigenesis such as HDAC6 and Pin1.
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Universidad Autónoma de Madrid, 28049 Madrid, Spain; Instituto de Investigación Sanitaria La Princesa, 28006 Madrid, Spain; Molecular Oncology and Nutritional Genomics of Cancer, Madrid Institute of Advanced Studies-Food Institute, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Nogués
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Universidad Autónoma de Madrid, 28049 Madrid, Spain; Instituto de Investigación Sanitaria La Princesa, 28006 Madrid, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Reglero
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Universidad Autónoma de Madrid, 28049 Madrid, Spain; Instituto de Investigación Sanitaria La Princesa, 28006 Madrid, Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: Rivas
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Salcedo
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Universidad Autónoma de Madrid, 28049 Madrid, Spain; Instituto de Investigación Sanitaria La Princesa, 28006 Madrid, Spain.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Lafarga
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Neves
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Universidad Autónoma de Madrid, 28049 Madrid, Spain; Instituto de Investigación Sanitaria La Princesa, 28006 Madrid, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Ramos
authors.affiliation: Laboratory of Pathology and Translational Oncology, Hospital la Paz Institute for Health Research, IdiPAZ, 28046 Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Mendiola
authors.affiliation: Department of Pathology, Hospital Universitario La Paz, School of Medicine, Universidad Autónoma de Madrid, IdiPaz, 28046 Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Berjón
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Kostas
authors.initials: K
authors.lastname: Stamatakis
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, CLS 0408, Boston, MA 02215, USA.
authors.forename: Xiao Zhen
authors.initials: XZ
authors.lastname: Zhou
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, CLS 0408, Boston, MA 02215, USA.
authors.forename: Kun Ping
authors.initials: KP
authors.lastname: Lu
authors.affiliation: Department of Pathology, Hospital Universitario La Paz, School of Medicine, Universidad Autónoma de Madrid, IdiPaz, 28046 Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Hardisson
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Universidad Autónoma de Madrid, 28049 Madrid, Spain; Instituto de Investigación Sanitaria La Princesa, 28006 Madrid, Spain. Electronic address: fmayor@cbm.csic.es.
authors.forename: Federico
authors.initials: F
authors.lastname: Mayor
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Universidad Autónoma de Madrid, 28049 Madrid, Spain; Instituto de Investigación Sanitaria La Princesa, 28006 Madrid, Spain. Electronic address: ppenela@cbm.csic.es.
authors.forename: Petronila
authors.initials: P
authors.lastname: Penela
mesh_terms: D000107:Acetylation; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008822:Mice, Transgenic; D008954:Models, Biological; D000072340:NIMA-Interacting Peptidylprolyl Isomerase / Q000378:metabolism*; D011379:Prognosis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D047368:Tumor Burden
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D034741:RNA, Small Interfering; D054769:G-Protein-Coupled Receptor Kinase 2; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: Acetylation; Breast transformation; Cancer; GRK2; HDAC6; Pin1