Cis-acting super-enhancer lncRNAs as biomarkers to early-stage breast cancer

• Published in: Breast cancer research : BCR Vol. 23; no. 1; pp. 101 - 18
• Main Authors: Ropri, Ali S., DeVaux, Rebecca S., Eng, Jonah, Chittur, Sridar V., Herschkowitz, Jason I.
• Format: Journal Article
• Language: English
• Published: London BioMed Central 30.10.2021; BioMed Central Ltd; BMC
• Subjects: Analysis; Biomarkers, Tumor - genetics; Biomedical and Life Sciences; Biomedicine; Breast cancer; Breast cancer progression; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer; Cancer Research; Cancer screening; Carcinoma, Ductal; Carcinoma, Ductal, Breast - genetics; Carcinoma, Ductal, Breast - pathology; Carcinoma, Intraductal, Noninfiltrating - genetics; Carcinoma, Intraductal, Noninfiltrating - pathology; Cell Line; Development and progression; Diagnosis; Disease Progression; Ductal carcinoma in situ; Enhancer Elements, Genetic - genetics; Enhancers; Estrogen receptors; Estrogens; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Genetic aspects; Genomes; Genomics; Humans; Invasiveness; Localization; Mammography; Medical research; Medicine, Experimental; Membrane Proteins - genetics; Metastases; Metastasis; MicroRNAs - genetics; NF-κB protein; Non-coding RNA; Oncology; Patients; Prevention; Protein folding; Receptors, Estrogen - metabolism; Research Article; RNA polymerase; RNA, Long Noncoding - genetics; Signal transduction; Super-enhancer long non-coding RNAs; Super-enhancers; Surgical Oncology; Therapeutic targets; Transcription; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology; Ductal carcinoma in situ; Super-enhancers; Super-enhancer long non-coding RNAs; Breast cancer progression
• ISSN: 1465-542X; 1465-5411; 1465-542X
• DOI: 10.1186/s13058-021-01479-8

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. Recent studies show 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 With an integrative analysis of enhancer loci with global expression of SE-lncRNAs in the MCF10A 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 The Cancer Genome Atlas (TCGA) database, we have unveiled 27 clinically relevant 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 RP11-379F4.4 and RP11-465B22.8 as potential markers of progression of DCIS to IDC through regulation of the expression of their neighboring genes (RARRES1 and miR-200b, respectively). Moreover, we classified 403 super-enhancer regions in MCF10A normal cells, 627 in AT1, 1053 in DCIS, and 320 in CA1 cells. Comparison analysis of acquired/lost super-enhancer regions with super-enhancer regions classified in 47 ER positive patients, 10 triple negative breast cancer (TNBC) patients, and 11 TNBC 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.