Abstract 464: Chromatin associated long non-coding RNAs involved in dormancy for late recurrence of ER-positive breast cancer

Abstract

Abstract Late recurrence is one of the major problems for hormone receptor-positive breast cancer patients. It is suggested that the risk of recurrence may be maintained by cancer cells that have been already disseminated in the body at surgery. They enter long-term dormancy, thus evade immune surveillance and become resistant to therapies. The detailed molecular mechanism for this process is largely unknown.Nuclear long noncoding RNAs, which are not translated to proteins, often function as epigenetic regulators and determine the phenotype of cells and individuals. We found that a cluster of long noncoding RNAs, ELEANORS, is specifically expressed in ER (estrogen receptor)-positive recurrent breast cancer cells, forms a molecular condensate (RNA cloud) in the nucleus, and activates the ESR1 gene that encodes ER. ELEANORS define a large chromatin domain, the 0.7 Mb topologically associated domain (TAD), which contains the ESR1 and three other breast-cancer-associated genes. ELEANORS also regulates the three-dimensional genome architecture. They mediate a long-range chromatin interaction of ESR1 and FOXO3 genes, which are 42.9 Mb apart, and contribute to their cooperatively activate transcription, equilibrating cell proliferation (ESR1) and apoptosis (FOXO3). Upon ELEANOR knockdown, the ELEANOR clouds are disappeared, and ESR1 gene transcription is repressed. Further, the two genes are dissociated and only the FOXO3 gene remains transcriptionally active, resulting in the induction of apoptosis.Further analysis of clinical specimens revealed that ELEANOR expression in primary tumors correlates with recurrences over 5 years after surgeries, suggesting that ELEANORs are involved in late recurrence. We also found that ELEANOR activates transcription of CD44, a breast cancer stem cell marker gene. Cancer stem cell maintenance and equilibration of proliferation and apoptosis by ELEANOR may be involved in long-term tumor dormancy in late recurrence. This study suggests the possibility of ELEANORS as a biomarker to predict late recurrence, as well as a therapeutic target for ER-positive breast cancer. (References)Abdalla, MOA. et al., Nat. Commun, 10, 3778 (2019) Tomita, S. et al., Nat. Commun, 6, 6966 (2015) Citation Format: Noriko Saitoh, Maierdan Palihati, Hiroaki Tachiwana. Chromatin associated long non-coding RNAs involved in dormancy for late recurrence of ER-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 464.