Program in Systems Biology; Graduate School of Biomedical Sciences
Amino Acids, Peptides, and Proteins | Cancer Biology | Cell Biology | Enzymes and Coenzymes | Genetic Phenomena | Neoplasms | Nucleic Acids, Nucleotides, and Nucleosides
Long non-coding RNAs (lncRNAs) play key roles in the regulation of breast cancer initiation and progression. LncRNAs are differentially expressed in breast cancer subtypes. Basal-like breast cancers are generally poorly differentiated tumors, are enriched in embryonic stem cell signatures, lack expression of estrogen receptor, progesterone receptor, and HER2 (triple-negative breast cancer), and show activation of proliferation-associated factors. We hypothesized that lncRNAs are key regulators of basal breast cancers. Using The Cancer Genome Atlas, we identified lncRNAs that are overexpressed in basal tumors compared to other breast cancer subtypes and expressed in at least 10% of patients. Remarkably, we identified lncRNAs whose expression correlated with patient prognosis. We then evaluated the function of a subset of lncRNA candidates in the oncogenic process in vitro. Here, we report the identification and characterization of the chromatin-associated lncRNA, RP11-19E11.1, which is upregulated in 40% of basal primary breast cancers. Gene set enrichment analysis in primary tumors and in cell lines uncovered a correlation between RP11-19E11.1 expression level and the E2F oncogenic pathway. We show that this lncRNA is chromatin-associated and an E2F1 target, and its expression is necessary for cancer cell proliferation and survival. Finally, we used lncRNA expression levels as a tool for drug discovery in vitro, identifying protein kinase C (PKC) as a potential therapeutic target for a subset of basal-like breast cancers. Our findings suggest that lncRNA overexpression is clinically relevant. Understanding deregulated lncRNA expression in basal-like breast cancer may lead to potential prognostic and therapeutic applications.
Breast cancer, Non-coding RNAs, Predictive markers, Tumour heterogeneity
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Copyright © The Author(s) 2020. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
DOI of Published Version
Giro-Perafita A, Luo L, Khodadadi-Jamayran A, Thompson M, Akgol Oksuz B, Tsirigos A, Dynlacht BD, Sánchez I, Esteva FJ. LncRNA RP11-19E11 is an E2F1 target required for proliferation and survival of basal breast cancer. NPJ Breast Cancer. 2020 Jan 6;6:1. doi: 10.1038/s41523-019-0144-4. PMID: 31934613; PMCID: PMC6944689. Link to article on publisher's site
NPJ breast cancer
Giro-Perafita A, Luo L, Khodadadi-Jamayran A, Thompson M, Akgol-Oksuz B, Tsirigos A, Dynlacht BD, Sanchez I, Esteva FJ. (2020). LncRNA RP11-19E11 is an E2F1 target required for proliferation and survival of basal breast cancer. Open Access Publications by UMMS Authors. https://doi.org/10.1038/s41523-019-0144-4. Retrieved from https://escholarship.umassmed.edu/oapubs/4137
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
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