Abstract 1433: Roles of noncoding RNAs in tumor dormancy of breast cancer recurrence

Abstract The vast majority of nuclear long non-coding RNAs (lncRNAs) are expressed in a cell type- or disease-specific manner. They often function as epigenetic factors, and are involved in higher-order chromatin structure [1-3]. Dysregulation of lncRNAs sometimes results in diseases, but the detailed mechanisms remain to be investigated.We have identified ELEANORS (ESR1 locus enhancing and activating non-coding RNAs), a cluster of lncRNAs in a model of endocrine therapy-resistant estrogen receptor (ER)-positive breast cancer, the LTED (long-term estrogen deprivation) cells [4]. ELEANORS are transcribed from a large chromatin domain including the gene encoding ER, ESR1. They associate with chromatin, and form a molecular condensate, the ELEANOR cloud, which is required for ESR1 gene activation. C-technologies, including Hi-C, revealed that ELEANORS define a chromatin domain, TAD (topologically associating domain) of about 0.7 Mb [5]. They also equilibrate cell growth and apoptosis by mediating a long-range chromatin interaction between the ESR1 and FOXO3 genes. The active transcription of the ESR1 locus with ELEANORS may represent frequent RNA polymerase II loading to the locus by a novel transcription initiation mechanism.Analysis of clinicopathological features of ELEANORS using patient tissues revealed that ELEANOR expression in primary tumors positively correlates with late recurrence [6]. Further, cancer stem cell populations that are involved in tumor dormancy for late recurrence were increased in LTED cells. They were decreased upon the ELEANOR knockdown, and the transcription level of the CD44 gene, a stem cell marker, also decreased. The ELEANOR and CD44 genes were frequently co-localized in the LTED cells. Thus, ELEANORS may be involved in stem cell maintenance through chromatin interactions. Our results suggest that nuclear lncRNAs are involved in 3D genome structure and pathological mechanisms. Citation Format: Noriko Saitoh, Maierdan Palihati, Hiroaki Tachiwana, Tomoko Fujita. Roles of noncoding RNAs in tumor dormancy of breast cancer recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1433.