Activation of the YY1-UGT2B7 Axis Promotes Mammary Estrogen Homeostasis Dysregulation and Exacerbates Breast Tumor Metastasis.

Abstract

Metastasis is the most common pathway of cancer death. The lack of effective predictors of breast cancer 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. In this study, tandem mass tag quantitative proteomics technology was used to detect protein content in primary breast tumor tissue samples from patients with metastatic and nonmetastatic breast cancer at diagnosis. We found that the high expression of yin-yang 1(YY1) is strongly associated with poor prognosis in high-grade breast cancer. YY1 expression was detected in both clinical tumor tissue samples and tumor tissue samples from mammary-specific polyomavirus middle T antigen overexpression mouse model mice. We demonstrated that upregulation 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 UGT2B7 mRNA 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, and the abnormal accumulation of estrogen, especially 4-OHE2, promotes the migration and invasion of breast cancer cells, ultimately causing the development of breast cancer metastasis. In conclusion, YY1 can regulate the UGT2B7-estrogen metabolic axis and induce disturbances in estrogen metabolism in breast tumors, ultimately leading to breast cancer metastasis. Disturbances in estrogen metabolism in the breast tissue may be an important risk factor for breast tumor progression and metastasis SIGNIFICANCE STATEMENT: In this study, we propose for the first time a regulatory relationship between YY1 and the UGT2B7/estrogen metabolism axis 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.