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Estrogen receptor α (ERα) is the most common clinical marker used for breast cancer prognosis and the classification of breast cancer subtypes. Clinically, patients with estrogen receptor-positive breast cancer can receive endocrine therapy. However, resistance to endocrine therapy has become an urgent clinical problem. A large number of previous studies have proven that posttranslational modification of the estrogen receptor is significantly related to endocrine therapy resistance. RNF2 is a member of the RING finger protein family that functions as an E3 ubiquitin ligase. Several studies have clarified that RNF2 is a critical regulator of ERα transcriptional regulation. In our current study, we identified RNF2 as an important posttranslational modification regulator of the estrogen receptor. RNF2 depletion inhibited breast cancer cell progression and ERα signaling activity. TCGA data analysis indicated that RNF2 was elevated in breast malignancies, while RNF2 depletion could drastically inhibit estrogen response gene expression on a whole-genome scale. TCGA data analysis revealed that RNF2 was positively correlated with ERα target gene expression. Further mechanistic studies showed that RNF2 was mainly localized in the nucleus and associated with ERα. The association increased ERα stability by inhibiting ERα K48-linked polyubiquitination. In conclusion, our study implicates nongenomic regulation by RNF2 on ERα protein stability and suggests that targeting RNF2 could be a promising strategy for breast cancer treatments.

The ubiquitin ligase RNF2 stabilizes ERα and modulates breast cancer progression