ObjectiveTo investigate whether Osteoglycin (OGN) gene inhibits the proliferation of Luminal breast cancer cells by up-regulating the expression of estrogen receptor (ER). Methods① Ualcan online database was used to analyze the expression of OGN in the breast cancer, and Kaplan-Meier Plotter was used to analyze the effect of OGN on the prognosis of patients with breast cancer. The median OGN mRNA expression level was taken as the cut-off point for high or low OGN expression. ② The expression of OGN mRNA in the Luminal breast cancer tissue of clinical case was examined using real time quantitative PCR (qRT-PCR). ③ Up-regulation of OGN expression in the Luminal breast cancer cell lines MCF-7 and T47D cells by transfection of overexpressing OGN plasmid, the expressions of OGN and ER were detected by qRT-PCR and Western blot, respectively. CCK8 assay and colony formation assay were applied to detect the cell proliferation and colony formation of Luminal breast cancer cells. ④ siRNA transfection was used to interfere with the expression of ER (ESR1) of breast cancer cells in the overexpressing OGN of breast cancer cells, then the CCK8 assay was used to detect the proliferation ability of the breast cancer cell lines after down-regulating the expression of ER in the overexpressing OGN patients. Results① The results of Ualcan online database showed that the expression of OGN mRNA in the breast cancer tissues of different types of breast cancer was lower than that in the normal breast tissues (P<0.001), and which was highest in the Luminal breast cancer tissues (P<0.001). The Kaplan-Meier Plotter prognosis analysis showed that in all breast cancer or Luminal breast cancer patients, the prognosis of patients with high OGN expression was better than those with low OGN expression (P=0.000 14, P=0.001 80). ② The OGN mRNA expression was decreased in the 30 Luminal breast cancer samples as compared with the corresponding adjacent normal breast tissues (t=4.774, P=0.000 019). ③ The expressions of OGN and ER in the MCF-7 and T47D cells were up-regulated after transfection of overexpressing OGN plasmid (P=0.000 002, P=0.000 001). The cell proliferation was inhibited (P<0.05) and the number of cell clones was decreased significantly (P<0.05). ④ After transient transfection of siRNA interfered with breast cancer cell lines of overexpressing OGN, ER mRNA level decreased (P<0.05), and cell proliferation ability increased significantly (P<0.05). Conclusion OGN could exert a tumor suppressor effect in Luminal breast cancer by mediating expression of ER.