Objective:To investigate the effect of miR-503 targeting CBX2 on drug resistance of breast cancer MDA-MB-231 cells and its potential mechanism.Methods:miR-con group, miR-503 group, si-con group, two groups of si-chromosome homologues (CBX), anti-miR-con group, anti-miR-503 group, miR-503+pcDNA group, miR-503+pcDNA-CBx2 group were set up. Real-time quantitative fluorescence polymerase chain reaction (qRT-PCR) was used to detect the expression levels of miR-503 and CBX2 mRNA. Western blot was used to detect protein expression. Cell activity was detected by MTT assay. The targeted regulatory relationship was detected by double luciferase assay.Results:Compared with normal breast cells HBL-100 (1.02±0.09), the expression level of miR-503 in breast cancer cells MCF-7 (0.41±0.05), MDA-MB-231 (0.25±0.03) and BT474 (0.35±0.04) was significantly decreased. The expression levels of CBX2 mRNA in MCF-7, MDA-MB-231 and BT474 cells were (4.02±0.35), (4.62±0.36) and (3.47±0.33), respectively. The expression levels of CBX2 protein in MCF-7, MDA-MB-231 and BT474 cells were (0.64±0.07), (0.74±0.05) and (0.68±0.06), respectively. The mRNA and protein contents of CBX2 in normal breast cells HPL-100 were (1.01±0.08) and (0.40±0.04), respectively, and the expression of CBX2 in breast cancer cells was significantly higher than that in normal breast cells ( P<0.05). Overexpression of miR-503 (3.64± 0.30) and silting of CBX2 inhibited proliferation, migration and invasion of MDA-MB-231 cells, and inhibited CBX2 (0.26±0.03), cyclin-dependent kinases, CDK) 4 (0.32± 0.03), Cyclin (CCN) D1 (0.58±0.03), matrix metalloproteinases (matrix metalloproteinases), MMP-2 (0.32±0.03) and MMP-9 (0.32±0.04) ( P<0.05). miR-503 targeted the expression of CBX2, and overexpression of CBX2 (0.75±0.03) could reverse the proliferation and drug resistance of miR-503 to MDA-MB-231 breast cancer cells. Conclusion:miR-503 may inhibit the proliferation, migration and invasion of breast cancer cells by down-regulating the expression of CBX2.