Cyclind1Protein Plays Different Roles In Modulating Chemoresponses In MCF7and MDA-MB231Cells

BackgroundCyclin D1is an essential sensor and activator of cell cycle initiation andprogression; overexpression of cyclinD1is linked to various human cancersincluding breast cancer. The elevated cyclinD1in some types of cancers is believedto be associated with tumor progression and response to systemic treatments.AimsIn this study, we anticipate to address the questions in human breast cancer;the function of cyclinD1in mediating chemoresponses; and the signaling pathwaycooperating with cyclinD1to interfere with the drug functions.Materials and MethodsUsing the cell clones concurrent ectopic expression of the wild-type orK112E-mutated human cyclinD1protein in the MCF7and MDA-MB231(MB231)breast cancer cells to study the function of cyclinD1in responses to thechemotherapeutic treatments. Three drugs, cisplatin (CDDP),5-fluorouracil (5-FU), and Gemzar were used in this study; the3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cell cycle and cell death analysis,clonogenic survival assay, acridine orange (AO)/ethidium bromide (EB) staining,and Western blot assay were conducted to evaluate the drugs’ effects in the cellclones.ResultsThe cell clones expressing the D1protein in MCF7and MB231cells result indistinct effects on the responses to chemotherapeutic treatments. Particularly withGemzar, ectopic expression of cyclinD1protein in MCF7cells results in apotentiated effect, which is CDK4kinase activity dependent; whereas in MB231cells, an opposite effect was observed. Moreover, our results suggested that thedistinct chemosensitivities among those cell clones were not resulted fromaccelerated cell cycle, cell proliferation driven by the cyclinD1CDK4/6-Rb-E2Fsignaling chain, rather, they were results of the cell cycle-independent functions ledby cyclinD1alone or in complex with CDK4.ConclusionsOur results suggest that the functions of cyclinD1protein in modulatingchemoresponses in the MCF7and MB231cells are independent to its function ascell cycle initiator through activation of CDK4/6. Furthermore, the signalsmodulated by cyclinD1upon treatment are determined by the drug and the cellularnetwork.