circRNA-SFMBT2 orchestrates ER & alpha; activation to drive tamoxifen resistance in breast cancer cells

Dysregulated ER & alpha; signaling is responsible for endocrine resistance and eventual relapse in patients with estrogen receptor-positive (ER+) breast cancer. Thus, identifying novel ER & alpha; 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 ER & alpha; protein level, implying a regulatory role for circRNA-SFMBT2 in ER & alpha; 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 ER & alpha; and allows it to interact with the AF2 and DBD domains of ER & alpha;, enforcing recruitment of RNF181 to the AF1 domain of ER & alpha;. Furthermore, the circRNA-SFMBT2/RNF181 axis differentially regulated K48-linked and K63-linked ubiquitination of ER & alpha; to enhance ER & alpha; stability, resulting in increased expression of ER & alpha; target genes and tumor progression. In summary, circRNA-SFMBT2 is an important regulator of ER & alpha; signaling, and antagonizing circRNA-SFMBT2 expression may constitute a potential therapeutic strategy for breast cancer.

Automated summary

circRNA-SFMBT2 is highly expressed in ER+ breast cancer cells and is associated with tumor size growth and poor prognosis. It positively correlates with ERα protein level and promotes cell growth and tamoxifen resistance. Inhibiting circRNA-SFMBT2 expression may be a potential therapeutic strategy for breast cancer.