title: Cyclin G2 promotes cell cycle arrest in breast cancer cells responding to fulvestrant and metformin and correlates with patient survival.
abstract: Definition of cell cycle control proteins that modify tumor cell resistance to estrogen (E2) signaling antagonists could inform clinical choice for estrogen receptor positive (ER+) breast cancer (BC) therapy. Cyclin G2 (CycG2) is upregulated during cell cycle arrest responses to cellular stresses and growth inhibitory signals and its gene, CCNG2, is directly repressed by E2-bound ER complexes. Our previous studies showed that blockade of HER2, PI3K and mTOR signaling upregulates CycG2 expression in HER2+ BC cells, and that CycG2 overexpression induces cell cycle arrest. Moreover, insulin and insulin-like growth factor-1 (IGF-1) receptor signaling strongly represses CycG2. Here we show that blockade of ER-signaling in MCF7 and T47D BC cell lines enhances the expression and nuclear localization of CycG2. Knockdown of CycG2 attenuated the cell cycle arrest response of E2-depleted and fulvestrant treated MCF7 cells. These muted responses were accompanied by sustained inhibitory phosphorylation of retinoblastoma (RB) protein, expression of cyclin D1, phospho-activation of ERK1/2 and MEK1/2 and expression of cRaf. Our work indicates that CycG2 can form complexes with CDK10, a CDK linked to modulation of RAF/MEK/MAPK signaling and tamoxifen resistance. We determined that metformin upregulates CycG2 and potentiates fulvestrant-induced CycG2 expression and cell cycle arrest. CycG2 knockdown blunts the enhanced anti-proliferative effect of metformin on fulvestrant treated cells. Meta-analysis of BC tumor microarrays indicates that CCNG2 expression is low in aggressive, poor-prognosis BC and that high CCNG2 expression correlates with longer periods of patient survival. Together these findings indicate that CycG2 contributes to signaling networks that limit BC.
authors.affiliation: a Department of Pharmacology , University of California , Davis , CA , USA.|b Department of Pharmacology , University of Iowa , Iowa City , IA , USA.|c Department of Internal Medicine , Division of Hematology and Oncology, University of California Davis , Sacramento , CA , USA.
authors.forename: Maike
authors.initials: M
authors.lastname: Zimmermann
authors.affiliation: b Department of Pharmacology , University of Iowa , Iowa City , IA , USA.
authors.forename: Aruni P S
authors.initials: AP
authors.lastname: Arachchige-Don
authors.affiliation: a Department of Pharmacology , University of California , Davis , CA , USA.
authors.forename: Michaela S
authors.initials: MS
authors.lastname: Donaldson
authors.affiliation: a Department of Pharmacology , University of California , Davis , CA , USA.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Patriarchi
authors.affiliation: a Department of Pharmacology , University of California , Davis , CA , USA.|b Department of Pharmacology , University of Iowa , Iowa City , IA , USA.
authors.forename: Mary C
authors.initials: MC
authors.lastname: Horne
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D056767:Cyclin G2 / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D018572:Disease-Free Survival; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D000077267:Fulvestrant; D055785:Gene Knockdown Techniques; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D034622:RNA Interference; D011960:Receptors, Estrogen / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D056767:Cyclin G2; D004967:Estrogens; D011960:Receptors, Estrogen; D016160:Retinoblastoma Protein; D000077267:Fulvestrant; D004958:Estradiol; D008687:Metformin; D019908:Proto-Oncogene Proteins c-raf; C501013:CDK10 protein, human; D018844:Cyclin-Dependent Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: CCNG2; CDK10; Cell Cycle Arrest; Estrogen Deprivation; Fulvestrant; IGF-1R; Insulin; Metformin; RAF/MEK/MAPK pathway; Tamoxifen-Resistant