<i>ERINA</i> Is an Estrogen-Responsive LncRNA That Drives Breast Cancer through the E2F1/RB1 Pathway.

Abstract

Resistance to therapeutic drugs is a major challenge in the treatment of cancers, including breast cancer. Long noncoding RNAs (lncRNA) are known to have diverse physiologic and pathophysiologic functions, including in cancer. In searching for lncRNA responsible for cancer drug resistance, we identified an intergenic lncRNA <i>ERINA</i> (estrogen inducible lncRNA) as a novel lncRNA highly expressed in multiple cancer types, especially in estrogen receptor-positive (ER⁺) breast cancers. Expression of <i>ERINA</i> was inversely correlated with survival of patients with ER⁺ breast cancer and sensitivity to CDK inhibitor in breast cancer cell lines. Functional characterization established <i>ERINA</i> as an oncogenic lncRNA, as knockdown of <i>ERINA</i> in breast cancer cells inhibited cell-cycle progression and tumor cell proliferation <i>in vitro</i> and xenograft tumor growth <i>in vivo</i>. In contrast, overexpression of <i>ERINA</i> promoted cell growth and cell-cycle progression. <i>ERINA</i> promoted cell-cycle progression by interacting with the E2F transcription factor 1 (E2F1), which prevents the binding of E2F1 to the tumor suppressor retinoblastoma protein 1 (RB1). <i>ERINA</i> also functioned as an estrogen and ER-responsive gene, and an intronic ER-binding site was identified as an enhancer that mediates the transactivation of <i>ERINA</i>. In summary, <i>ERINA</i> is an estrogen-responsive oncogenic lncRNA that may serve as a novel biomarker and potential therapeutic target in breast cancer. SIGNIFICANCE: These findings identify <i>ERINA</i> as an estrogen-responsive, oncogenic lncRNA, whose elevated expression may contribute to drug resistance and poor survival of patients with ER⁺ breast cancer.