Comprehensive analysis of long non-coding RNAs in human breast cancer clinical subtypes
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Xiaoping Su1,*, Gabriel G. Malouf2,*, Yunxin Chen3, Jianping Zhang1, Hui Yao1, Vicente Valero3, John N. Weinstein1, Jean-Philippe Spano2, Funda Meric-Bernstam4, David Khayat2 and Francisco J. Esteva5
1 Departments of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2 Groupe Hospitalier Pitié-Salpêtrière, Department of Medical Oncology, University Pierre and Marie Curie (Paris VI), Institut Universitaire de Cancérologie, AP-HP, Paris, France
3 Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
4 Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
5 Breast Medical Oncology Program, New York University Cancer Institute, New York, NY, USA
* These authors contributed equally to this work
Xiaoping Su, email:
Keywords: breast cancer, enhancers, expression profiling, lncRNA, RNA-Seq
Received: July 13, 2014 Accepted: September 07, 2014 Published: September 08, 2014
Accumulating evidence highlights the potential role of long non-coding RNAs (lncRNAs) as biomarkers and therapeutic targets in solid tumors. However, the role of lncRNA expression in human breast cancer biology, prognosis and molecular classification remains unknown. Herein, we established the lncRNA profile of 658 infiltrating ductal carcinomas of the breast from The Cancer Genome Atlas project. We found lncRNA expression to correlate with the gene expression and chromatin landscape of human mammary epithelial cells (non-transformed) and the breast cancer cell line MCF-7. Unsupervised consensus clustering of lncRNA revealed four subgroups that displayed different prognoses. Gene set enrichment analysis for cis- and trans-acting lncRNAs showed enrichment for breast cancer signatures driven by master regulators of breast carcinogenesis. Interestingly, the lncRNA HOTAIR was significantly overexpressed in the HER2-enriched subgroup, while the lncRNA HOTAIRM1 was significantly overexpressed in the basal-like subgroup. Estrogen receptor (ESR1) expression was associated with distinct lncRNA networks in lncRNA clusters III and IV. Importantly, almost two thirds of the lncRNAs were marked by enhancer chromatin modifications (i.e., H3K27ac), suggesting that expressed lncRNA in breast cancer drives carcinogenesis through increased activity of neighboring genes. In summary, our study depicts the first lncRNA subtype classification in breast cancer and provides the framework for future studies to assess the interplay between lncRNAs and the breast cancer epigenome.
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