circRNA-SFMBT2 orchestrates ERα activation to drive tamoxifen resistance in breast cancer cells.

Dysregulated ERα signaling is responsible for endocrine resistance and eventual relapse in patients with estrogen receptor-positive (ER) breast cancer. Thus, identifying novel ERα regulators is necessary to fully understand the mechanisms of endocrine resistance. Here, we identified circRNA-SFMBT2 to be highly expressed in ER breast cancer cells in comparison to ER cells and found that high circRNA-SFMBT2 levels were related to larger tumor size and poor prognosis in patients with ER breast cancer. In vitro and in vivo experiments confirmed that the circRNA-SFMBT2 level was positively correlated with the ERα protein level, implying a regulatory role for circRNA-SFMBT2 in ERα signaling. Moreover, we found that circRNA-SFMBT2 biogenesis could be facilitated via RNA-binding protein quaking (QKI), and biologically elevated circRNA-SFMBT2 expression promoted cell growth and tamoxifen resistance in ER breast cancer. Mechanistically, circRNA-SFMBT2 exhibits a specific tertiary structure that endows it with a high binding affinity for ERα and allows it to interact with the AF2 and DBD domains of ERα, enforcing recruitment of RNF181 to the AF1 domain of ERα. Furthermore, the circRNA-SFMBT2/RNF181 axis differentially regulated K48-linked and K63-linked ubiquitination of ERα to enhance ERα stability, resulting in increased expression of ERα target genes and tumor progression. In summary, circRNA-SFMBT2 is an important regulator of ERα signaling, and antagonizing circRNA-SFMBT2 expression may constitute a potential therapeutic strategy for breast cancer.