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Objective: To better understand genetic characteristics and identify the genetic variations of metastatic breast cancer（BC）that can serve as a specific treatment target and biomarker.Methods: 1.Analyzing the genetic and epigenetic differences between latestage and early-stage breast CA with postoperative DFS ＞ 5 years with the genome and methylome data of Cancer Genome Atlas（TCGA）to find the specific mutation genes related to breast CA metastasis.2.Using breast CA patient data from datasets including TCGA、,MEXPRESS、c Bio Portal,and bioinformatics,the analysis was performed to verify the association between the epigenetic changes in the ADCY4 gene and the breast CA.Results: 1.At the SNV level,EGF,MYO3 B,LAMC2,and Sema4 D were specific high-frequency Mutation Genes in estrogen receptor-positive metastatic breast CA（MBC）（mutation rate ≥ 15.78%）.At the DNA methylation level,ADCY4 has a significant（P = 0.008）methylation site located in the gene’s body.2.In Finak’s dataset,the invasive breast CA（IBC）stroma showed 2.27-fold increased expression of ADCY4;however,in primary breast CA,this was downregulated by 4.12-fold（p=1.00e-12）.The expression of ADCY4 m RNA in breast CA was negatively correlated with its promoter methylation.ADCY4 expression was significantly decreased,and a correlation between“Overall survival（OS）” and “relapse-free survival（RFS）” was appreciated in breast-CA with different intrinsic subtypes.It is found that the downregulation of ADCY4 in breast-CA may be caused by the cycling AMP signaling pathway via an adenylate cyclase modulating G-protein coupled receptor.Conclusion: 1.The promoter methylation of ADCY4 and genetic polymorphisms in the genes for EGF,MYO3 B,LAMC2,and Sema4 D may be linked to the distant metastasis of ER+ breast CA.2.The ADCY4 might function as a tumor suppressor gene;hence,it is worth exploring further its biological role in cancer progression and tumorigenesis.According to the information presented here,ADCY4 may be used as a therapeutic target and a biomarker of prognosis for breast-CA