Activation of the YY1-UGT2B7 axis promotes mammary estrogen homeostasis dysregulation and exacerbates breast tumor metastasis .

Background Metastasis is the most common pathway of cancer death. The lack of effective predictors of breast metastasis is a pressing issue in clinical practice. Therefore, exploring the mechanism of breast cancer metastasis to uncover reliable predictors is very important for the clinical treatment of breast cancer patients. Methods TMT quantitative proteomics technology was used to detect protein content in primary breast tumor tissue samples from patients with metastatic and non-metastatic breast cancer at diagnosis. Assays of scratch, transwell, chromatin immunoprecipitation assays, promoter luciferase assay were used to identify the molecular mechanisms. LC-MS/MS was applied to detect estrogen levels in tumor and serum samples. Results In this study, we found that the high expression of YY1 is strongly associated with poor prognosis in high-grade breast cancer. We also demonstrated that up-regulation of YY1 expression was closely associated with breast cancer metastasis and that high YY1 expression could promote the migratory invasive ability of breast cancer cells. Mechanistically, YY1 directly binds to the UGT2B7mRNA initiation sequence ATTCAT, thereby transcriptionally regulating the inhibition of UGT2B7 expression, UGT2B7 can regulate the development of breast cancer by regulating estrogen homeostasis in the breast, promote the migration and invasion of breast cancer cells, ultimately causing the development of breast cancer metastasis. Conclusions Disturbances in estrogen metabolism in the breast tissue may be an important risk factor for breast tumor progression and metastasis. YY1 can regulate the UGT2B7-estrogen metabolic axis and induce disturbances in estrogen metabolism in breast tumors, ultimately leading to breast cancer metastasis. Significance Statement In this study, we propose for the first time a regulatory relationship between YY1-UGT2B7 axis and the estrogen metabolic and explore the molecular mechanism. Our study shows that the YY1/UGT2B7/estrogen axis plays an important role in the development and metastasis of breast cancer. This study further elucidates the potential mechanisms of YY1-mediated breast cancer metastasis and the possibility and promise of YY1 as a predictor of cancer metastasis.