Abstract P5-12-09: Cis-acting super-enhancer lncRNAs as diagnostic markers to early-stage breast cancer

Abstract

Abstract Background: Increased breast cancer screening over the past four decades has led to a substantial rise in the diagnosis of ductal carcinoma in situ (DCIS).Although DCIS lesions precede invasive ductal carcinoma (IDC),they do not always transform into cancer. The current standard-of-care for DCIS is an aggressive course of therapy to prevent invasive and metastatic disease resulting in over-diagnosis and over-treatment. Thus, there is a critical need to identify functional determinants of progression of DCIS to IDC to allow discrimination between indolent and aggressive disease. Super-enhancers are regulatory regions of DNA that play critical roles in driving expression of genes that define cell fate decisions and importantly, their normal function can become co-opted during tumorigenesis. Recent studies have found that super-enhancers, in addition to promoting other gene transcription, are themselves transcribed producing super-enhancer associated long noncoding RNAs (SE-lncRNAs).These SE-lncRNAs can interact with their associated enhancer regions in cis and influence activities and expression of neighboring genes. Furthermore, they represent a novel, untapped group of therapeutic targets. Methods: The MCF10Abreast cancer progression series is composed of four cell lines that mimic the progression of normal cells (MCF10A)to atypia(AT1),to DCIS (DCIS),and finally, to IDC (CA1).With an integrative analysis of enhancer loci with global expression of SE-lncRNAs in the progression series, we have identified differentially expressed SE-lncRNAs which can identify mechanisms for DCIS to IDC progression. Furthermore, cross-referencing these SE-lncRNAs with patient samples in the TCGA database, we have unveiled 31clinicallyrelevant SE-lncRNAs that potentially interact with their enhancer to regulate nearby gene expression. To complement SE-lncRNA expression studies, we conducted an unbiased global analysis of super-enhancers that are acquired or lost in progression. Results: Here we designate SE-lncRNAs RP11-379F4.4and RP11-465B22.8as potential markers of progression of DCIS to IDC through regulation of the expression of their neighboring genes (RARRES1and miR200brespectively).Moreover, we classified 403super-enhancer regions in MCF10Anormal cells, 627in AT1,1053in DCIS, and 320in CA1cells. Comparison analysis of acquired/lost super-enhancer regions with super-enhancer regions classified in 47ER positive patients, 10TripleNegative Breast Cancer (TNBC)patients, and 11TNBC cell lines reveal critically acquired pathways including STAT signaling and NF-kB signaling. In contrast, protein folding and local estrogen production are identified as major pathways lost in progression. Conclusion: Collectively, these analyses identify differentially expressed SE-lncRNAs and acquired/lost super-enhancers in progression of breast cancer important for promoting DCIS lesions to IDC. Citation Format: Ali S Ropri, Rebecca Devaux, Jonah Eng, Sridar Chittur, Jason Herschkowitz. Cis-acting super-enhancer lncRNAs as diagnostic markers to early-stage breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-12-09.