Cyclin G2 Contributes to the Cell Cycle Arrest Response of Breast Cancer Cells to Estrogen Signaling‐Antagonists and the AMPK Agonist, Metformin

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Resistance to estrogen (E2) receptor (ER) antagonists limits long‐term abatement of ER+ breast cancer (BC). Defining cell cycle control proteins that modify tumor cell resistance to ER‐antagonists tamoxifen and fulvestrant will improve therapeutic approaches. Cyclin G2 (CycG2) is encoded by the ER repressed gene, CCNG2, and upregulated during cell cycle arrest responses to cellular stresses. Here we show that blockade of ER‐signaling enhances the expression and nuclear localization of CycG2 in E2‐dependent BC cell lines. Knockdown of CycG2 in E2‐deprived and fulvestrant‐treated MCF7 cells dampened their cell cycle arrest response. Moreover, loss of CycG2 increases phospho‐activation of MEK1 and inhibition of RB. Our work also indicates that CycG2 forms complexes with the CDK linked to inhibition of tamoxifen resistance and modulation of RAF/MEK/MAPK signaling, CDK10. We reported that signaling through insulin and IGF‐1R receptors strongly represses CycG2 expression. Recent studies suggest the insulin‐sensitizer metformin (MTFN) inhibits BC cell growth by promoting AMPK–mediated suppression of mTOR. Patients taking MTFN exhibit a dose‐dependent reduction in cancer risk. We found that MTFN treatment stimulates CycG2 expression and potentiates fulvestrant‐mediated upregulation of CycG2 and growth arrest of MCF7 cells. Moreover knockdown of CycG2 blunts MTFN‐enhancement of fulvestrant effects. Importantly, analysis of BC tumor microarrays indicates that CCNG2 transcripts are reduced in aggressive, poor‐prognosis BC and that high CCNG2 expression correlates with longer relapse free survival.