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 noncoding RNA (lncRNA) actin gamma 1 pseudogene 25 (AGPG) as a regulator of E2F1 activity in endocrine-resistant breast cancer. Expression of AGPG 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 patients with ERα+ breast cancer receiving endocrine therapy. The upregulation of AGPG mediated resistance to endocrine therapy and cyclin-dependent kinase 4/6 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 patients with breast cancer, E2F1 target genes were positively and negatively correlated with expression of AGPG and PURα, respectively. Coadministration 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.
Significance: Blockade of formation of the PURα/E2F1 complex by lncRNA AGPG activates E2F1 and promotes endocrine resistance, providing potential strategies for combatting endocrine-resistant breast cancer.
©2023 American Association for Cancer Research.