Cyclin G2 promotes cell cycle arrest in breast cancer cells responding to fulvestrant and metformin and correlates with patient survival
| Autor: | Aruni S. Arachchige-Don, Mary C. Horne, Tommaso Patriarchi, Michaela S. Donaldson, Maike Zimmermann |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cell cycle checkpoint Estrogen receptor Pharmacology Retinoblastoma Protein Estrogen Deprivation 0302 clinical medicine Receptors Insulin Phosphorylation Extracellular Signal-Regulated MAP Kinases Fulvestrant Cancer Cell Cycle Arrest Tumor Estradiol biology Retinoblastoma protein Cell cycle Metformin Cyclin-Dependent Kinases MEK Up-Regulation Protein Transport Receptors Estrogen Local Gene Knockdown Techniques 030220 oncology & carcinogenesis RNA Interference Female Signal transduction Signal Transduction medicine.drug Cyclin G2 Tamoxifen-Resistant Breast Neoplasms Disease-Free Survival Cell Line 03 medical and health sciences Cyclin D1 Cyclin-dependent kinase Cell Line Tumor Report Breast Cancer medicine Humans RAF/MEK/MAPK pathway Molecular Biology Cell Nucleus Mitogen-Activated Protein Kinase Kinases Estrogens MAPK pathway Cell Cycle Checkpoints RAF Cell Biology Estrogen Survival Analysis CCNG2 Proto-Oncogene Proteins c-raf Neoplasm Recurrence 030104 developmental biology biology.protein Cancer research Biochemistry and Cell Biology Neoplasm Recurrence Local IGF-1R CDK10 Developmental Biology |
| Zdroj: | Cell cycle (Georgetown, Tex.), vol 15, iss 23 |
| ISSN: | 1551-4005 1538-4101 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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