To the Editor: Breast cancer (BC) is the most common cancer in women, which affects 2.26 million people annually, with 680,000 fatalities. Around 70% of cases involve estrogen-activated estrogen receptors (ER), which promote tumor growth through gene regulation and cellular signaling. ER reactivation without ligands contributes to therapy resistance. Endocrine resistance in estrogen receptor-positive (ER+) breast tumors can result from mutations in ER, altered interactions with coactivators/corepressors, or crosstalk with growth factor receptors and oncogenic pathways.[1] Additionally, long non-coding RNAs (lncRNAs) are diverse molecules with distinct expression patterns in different cancer types, playing critical roles in tumorigenesis.[2] Notably, actin gamma 1 pseudogene (AGPG) is emerging as a noteworthy lncRNA that holds promise as a new therapeutic target intended for the effective management of endocrine-resistant BC. A recent study by Yu et al[3] identified 28 lncRNAs linked to endocrine resistance in BC cells. Among them, AGPG exhibited significant upregulation, particularly in luminal B (LumB) BC cells, and was linked to epigenetic modifications, suggesting its role in endocrine resistance in these cells. BC transcriptome data revealed elevated AGPG gene expression in all BC subtypes, particularly LumB and human epidermal growth factor receptor 2 (Her2) subtypes. Higher AGPG expression was linked to advanced-stage cancer, metastatic tumor, and higher-grade tumors. AGPG downregulation inhibited cell proliferation, colony formation, and G1-to-S phase transition, thereby causing cell cycle arrest in the G1 phase. This made the cells more responsive to Tamoxifen (TAM) and Fulvestrant (Ful) treatments. Critically, AGPG knockdown elevates Ful sensitivity in ESR1-Y537S mutant cells, highlighting a crucial role of AGPG in ESR1 mutant-mediated resistance to Ful.[3] The study emphasizes the need for further research to understand AGPG's role in ESR1 mutant-mediated resistance and potential therapeutic strategies [Figure 1①].Figure 1: AGPG drives endocrine resistance in breast cancer by disrupting the PURα/E2F1 complex, activating cell cycle genes (a detailed description is provided in the supplementary material, https://links.lww.com/CM9/C88). The figure was created using Biorender.com. Detailed legend of the figure is described in Supplementary material, https://links.lww.com/CM9/C88. AGPG: Actin gamma 1 pseudogene; BC: Breast cancer; CDK4/6i: CDK4/6 inhibitor; E2F1: E2F transcription factor 1; ER: Estrogen receptor; ERα+: Estrogen receptor-α positive; Ful: Fulvestrant; LARP4B: La ribonucleoprotein domain family member 4B; MCF7: Michigan Cancer Foundation-7; MEK: mitogen-activated protein kinase 1/2; miR-106b: microRNA-106b; PURα: Pur-alpha; SLIRP: Stem-loop interacting RNA binding protein; TSPYL5: Testis-specific Y-like protein 5; USP7: Ubiquitin-specific protease 7.AGPG expression was elevated in endocrine-resistant cells, and its suppression sensitizes them to treatment. AGPG knockdown inhibits the growth of resistant xenografts, making AGPG a potential therapeutic target for overcoming resistance and improving cancer treatments. Therefore, investigating AGPG's molecular mechanisms may lead to novel therapeutic strategies for CDK4/6i resistance [Figure 1②]. AGPGmediates E2F signaling via Pur-alpha (PURα)/E2F transcription factor 1 (E2F1) complex disruption.AGPG-knockdown MCF7 cell lines showed downregulation of about 2000 genes related to cell cycle processes, specifically E2Fs and v-myc avian myelocytomatosis viral oncogene homolog (MYC)-related pathways. Gene Set Enrichment Analysis confirmed reduced activity in the G2/M checkpoint, E2F targets, and MYC targets. AGPG overexpression had the opposite effect on these genes. The research suggests a potential connection between AGPG and MYC-related pathways in conferring endocrine resistance in BC [Figure 1⑥]. An RNA pulldown assay revealed the selective capture of a 40,000 protein by biotinylated AGPG, and identified 42 potential AGPG binding proteins, including 16 RNA binding proteins. The study confirmed an interaction between AGPG and PURα, a 39,000 DNA/RNA binding transcription factor. The interaction with PURα was specific to residues 1-215 of PURα, an essential region for its interactions with E2F1.[3] Furthermore, consistently reduced PURα mRNA expression was found in BC across different subtypes compared to normal tissues. High PURα protein levels were observed in the LumA subtype but low staining in LumA and LumB, while it was more prevalent in normal tissues and Her2+ breast tumors. Therefore, it would be interesting to check how AGPG regulates the interaction of PURα with E2F1 in Her2+ breast tumors. Interestingly, PURα expression is negatively correlated with sensitivity to endocrine therapeutics in ERα+ BC cell lines. Further investigation into this relationship for potential therapies are warranted.[3] RNA sequencing revealed that knocking down PURα led to the upregulation of cancer progression-associated, cell cycle regulation, and E2F signaling genes. Further experiments demonstrated that AGPG potentially sequesters PURα to activate E2F1 signaling. Disrupting this interaction by AGPG knockdown partially countered the effects on gene expression and cell proliferation, implying the involvement of other regulatory factors [Figure 1③]. Transcriptome analysis in BC datasets indicated that AGPG and PURα expression was linked to cell cycle regulation and oncogenic processes with potential implications for tumor progression. Collectively, AGPG interacts physically with the PURα protein to disrupt PURα/E2F1 complex, thereby activating cell cycle-related genes. Conclusively, this study reveals the interplay of AGPG with PURα, thereby disrupting the PURα/E2F1 complex, activating cell cycle-related genes, and implicating a connection with MYC-related pathways in endocrine resistance in BC.[3] Exploration of novel pathways in AGPG-mediated endocrine resistance. Their mass spectrometry analysis reveals that mitogen-activated protein 3 kinase kinase 19 (MAP3K19) interacts with AGPG and can activate the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway, which enhances ER-mediated gene transcription.[4] This discovery suggests that targeting the MAP3K19-mitogen-activated protein kinase 1/2 (MEK1/2)-ERK1/2 axis could be a potential therapeutic strategy for endocrine-resistant ER+ BC [Figure 1⑤]. Furthermore, recent findings highlight the identification of S6 kinase 1 (S6K1) amplification as a potential predictive biomarker for resistance to CDK4/6i.[5] This suggests potential crosstalk between the ERK1/2 and CDK4/6i resistance mechanisms. Ribosomal protein L26 (RPL26) exerts a regulatory role by attenuating the binding affinity between microRNA (miR)-27a and p53, thereby impeding microRNA-mediated downregulation of p53 expression. Notably, an examination of cells harboring different TP53 genotypes demonstrated that HCT-116 cells with TP53 knockout exhibited elevated AGPG levels in comparison to control.[6] This finding implies a possible inhibitory effect of p53 on AGPG expression. However, further research is necessary to comprehensively explore the role of AGPG in endocrine therapy. These results collectively shed light on the intricate regulatory network involving AGPG, miR-27a, and p53. Moreover, mouse double minute 2 (Mdm2) binding to RPL26 leads to its degradation, disrupts its interaction with p53 mRNA, and impairs p53 protein synthesis. RPL26 also prevents miR-27a binding to p53, while tumor growth factor-β1 dissociates RPL26 and eukaryotic elongation factor 1 alpha (eEF1A) from p53 mRNA, reducing p53 translation.[7] These findings emphasize the complex role of Mdm2–RPL26 interaction in regulating p53-dependent pathways in cellular stress responses. Mass spectrometry also identified a significant interaction between testis-specific Y-like protein 5 (TSPYL5); an AGPG interacting protein) and ubiquitin-specific protease 7 (USP7), where TSPYL5 reduces USP7's impact on p53, leading to decreased p53 levels and decreased activation of p53-target genes.[8]AGPG, a p53-regulated gene, shows a negative association with p53 expression and is linked to endocrine resistance in BC via E2F1.[4] Studying the interplay between AGPG, TSPYL5, and E2F1 is vital for understanding endocrine resistance and developing new BC therapies. Furthermore, findings on imipramine-mediated inhibition of cell cycle and DNA repair proteins could complement the understanding of AGPG-mediated endocrine resistance.[9] The impact of imipramine on E2F1, CDK1, Cyclin D1, and radiation sensitive 51 (RAD51) may provide insights into the regulation of AGPG-associated pathways and could potentially be explored as a therapeutic intervention for endocrine-resistant BC. miR-106b plays a crucial role in prostate cancer (PCa) by inhibiting apoptosis and affecting key regulators like p21 and E2F1. Its levels are inversely related to the expression of La ribonucleoprotein domain family member 4B (LARP4B). Overexpression of miR-106b in PCa cells suppresses cell viability, invasion, and migration by regulating factors like Kiel 67 (Ki67), matrix metalloproteinase-2 (MMP-2), cluster of differentiation 44 (CD44), and mothers against decapentaplegic homolog 2 (Smad2).[10] LARP4B's role in cell cycle control is implicated, particularly in osteosarcoma and PCa cell lines, through post-transcriptional regulation of key cell cycle proteins.[11] Investigating the interplay among AGPG, LARP4B, and E2F1 in endocrine resistance holds promise for understanding the mechanisms and potential therapies [Figure 1⑦]. SRA stem-loop interacting RNA binding protein (SLIRP) siRNA treatment in PCa cells increased Retinoblastoma protein (Rb) phosphorylation, cell proliferation, and the expression of cell cycle regulatory molecules.[12] This suggests the importance of studying the interaction between AGPG, SLIRP, and E2F1 in understanding endocrine resistance [Figure 1⑧]. AGPG has been described recently as a key player in promoting glycolysis and cancer progression,[6] suggesting a potential connection to endocrine resistance in BC. AGPG impedes the degradation of 6-Phosphofructo-2-Kinase/Fructose-2, 6-Biphosphatase 3, leading to increased glycolysis and cell cycle progression, making it a potential target for more effective therapies against drug-induced endocrine resistance in BC and other malignancies [Figure 1④]. Taken together, BC, particularly ER+ BC, remains a significant global health challenge. Understanding the mechanisms driving endocrine resistance is paramount for improving patient outcomes. We have reviewed recent research on the role of AGPG in mediating endocrine resistance in ER+ BC. However, several questions remain to be addressed (see supplementary material, https://links.lww.com/CM9/C88). By addressing the outstanding questions and pursuing these research prospects, we can contribute to a deeper understanding of BC biology and the development of more effective therapies. Funding The authors gratefully acknowledge the National Natural Science Foundation of China (No. 82371877). This study was funded in part by the Startup Foundation for Advanced Talents and Science and Technology Innovation Foundation at Yangzhou University (No. 137011856 to H.S.), the Distinguished Doctoral Program of Green Yang Golden Phoenix of Yangzhou City (No. 137012751 to S.Y.), the Talent Introduction Fund of Yangzhou University (No. 137012455 to S.Y.). Conflicts of interest None.
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