LncRNA AGPG Confers Endocrine Resistance in Breast Cancer by Promoting E2F1 Activity

Abstract

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.

Propofol‐induced LINC01133 inhibits the progression of colorectal cancer via miR‐186‐5p/NR3C2 axis

“…In addition, propofol can enhance the sensitivity of lung cancer cells to cisplatin by inhibiting the Wnt/β‐catenin pathway 33 . Over the past decade, significant attention has been devoted to the exploration of lncRNAs and their influence on the biological processes of malignant tumors 34,35 . Experimental evidence has validated the regulatory roles of certain lncRNAs in CRC progression, such as the inhibition of chemoresistance, mitigation of metastatic potential, and modulation of immune cell function 36–38 .…”

Purine-Rich Element Binding Protein Alpha, a Nuclear Matrix Protein, Has a Role in Prostate Cancer Progression

“…Recently, Yu et al reported that the expression of the long noncoding RNA (lncRNA) acting gamma 1 pseudogene 25 (AGPG) was increased in endocrine-resistant breast cancer cells by the epigenomic activation of the enhancer [52]. AGPG was upregulated, especially in patients with luminal B subtype breast cancers, and a high AGPG expression was associated with poor survival in estrogen receptor (ER)-positive breast cancers [52]. Interestingly, they identified that AGPG has a potential binding interaction with PURα in the nucleus [52].…”

“…AGPG was upregulated, especially in patients with luminal B subtype breast cancers, and a high AGPG expression was associated with poor survival in estrogen receptor (ER)-positive breast cancers [52]. Interestingly, they identified that AGPG has a potential binding interaction with PURα in the nucleus [52]. Previously, PURα has been shown to interfere with the transcriptional activation of the Sphase-specific gene dihydrofolate reductase (DHFR) by interacting with E2F1 and preventing its association with the E2F1 elements located within the DHFR promoter [53].…”

Association between urinary phthalates and phthalate metabolites and cancer risk: A systematic review and meta-analysis

“…A number of clinical studies suggested a strong correlation between exposure to environmental pollution and the incidence and mortality rates of cancer [ [16] , [17] , [18] ], which was consistent with results in animal models [ 19 , 20 ]. In addition, a series of studies have revealed that the disruption of the endocrine system plays significant roles in the development of breast cancer [ 21 ], prostate cancer [ 22 ], thyroid cancer [ 23 ], and endometrial cancer [ 24 ]. Moreover, endocrine therapy has been tried to treat these cancers mentioned above.…”