LncRNA AGPG confers endocrine resistance in breast cancer by promoting E2F1 activity

Resistance to endocrine therapy represents a major concern for patients with Estrogen receptor α positive (ERα+) breast Cancer. Endocrine therapy resistance is commonly mediated by activated E2F signaling. A better understanding of the mechanisms governing E2F1 activity in resistant cells could reveal strategies for overcoming resistance. Here, we identified the long non-coding RNA (lncRNA) actin gamma 1 pseudogene 25 (AGPG) as a regulator of E2F1 activity in endocrine resistant breast Cancer. Expression of EGPG was increased in endocrine-resistant breast Cancer cells, which was driven by epigenomic activation of an enhancer. AGPG was also abnormally upregulated in patient breast tumors, especially in the luminal B subtype, and high AGPG expression was associated with poor survival of ERα+ breast Cancer patients receiving endocrine therapy. The upregulation of AGPG mediated resistance to endocrine therapy and CDK4/6 inhibition in breast Cancer cells. Mechanistically, AGPG physically interacted with PURα, thus releasing E2F1 from PURα and leading to E2F1 signaling activation in ERα+ breast Cancer cells. In breast Cancer patients, E2F1 target genes were positively and negatively correlated with expression of AGPG and PURα, respectively. Co-administration of chemically modified AGPG siRNA and tamoxifen strongly suppressed tumor growth in endocrine resistant cell line-derived xenografts. Together, these results demonstrate that AGPG can drive endocrine therapy resistance and indicate that it is a promising biomarker and potential therapeutic target in breast Cancer.