Oncogene https://doi.org/10.1038/s41388-019-1040-y REVIEW ARTICLE Long noncoding RNAs and exosomal lncRNAs: classification, and mechanisms in breast cancer metastasis and drug resistance Hassan Yousefi 1 ● Maryam Maheronnaghsh 2 ● Fatemeh Molaei 3 ● Ladan Mashouri 4 ● Amir Reza Aref 5 ● Majid Momeny 6 ● Suresh K. Alahari 1 Received: 13 June 2019 / Revised: 4 September 2019 / Accepted: 20 September 2019 © The Author(s), under exclusive licence to Springer Nature Limited 2019 Abstract Breast cancer is the most common cancer, and the second cause of cancer-related deaths (after lung cancer) among women. Developing tumor metastasis and invasion is the most important cause of death in breast cancer patients. Several key factors participate in breast cancer metastasis including long noncoding RNAs (lncRNAs). lncRNAs are a category of cellular RNAs that are longer than 200 nucleotides in length. Accumulating evidence suggests that lncRNAs have the potential to be promising diagnostic, prognostic biomarkers and therapeutic targets in breast cancer. Understanding the role of lncRNAs and their mechanisms of functions might help to further discovery of breast cancer biological characteristics. In this review, we discuss physiological functions, epigenetic regulation, transcriptional regulation of lncRNAs, and their important role in tumor progression and metastasis. Some lncRNAs function as oncogenes and some function as tumor suppressors. Interestingly, recent reports depict that hypomethylation of promoters of lncRNAs play a pivotal role in cancer progression, suggesting the importance of epigenetic regulation. Furthermore, we discuss the role of lncRNAs in exosomes and their function in drug resistance, and therapeutic importance of exosomal lncRNAs in cancer biology. In summary, lncRNAs have a great potential to consider them as novel prognostic biomarkers as well as new therapeutic targets in breast cancer Introduction In humans, although 70% of the genome is transcribed to RNA, only about 2% of these transcripts are translated into proteins [1, 2]. The rest of the transcripts are defined as noncoding RNAs, which can be divided into two main groups; (1) short noncoding RNAs including microRNAs (miRNAs), small interfering RNAs (siRNAs), P-element- induced wimpy testis-interacting RNA and small nucleolar RNAs (snoRNAs); and (2), long noncoding RNAs (lncRNAs) [2]. Among these, short noncoding RNAs are mainly considered as negative regulators of gene expres- sion; while lncRNAs are a wide heterogeneous group that has not been well studied so far [3]. Many of these lncRNAs are shown by genome-wide association studies and impli- cated in a variety of human diseases including cancers [1, 3]. lncRNAs are defined as transcripts with a length of more than 200 bp and lack of open reading frames. lncRNAs share several common features with protein cod- ing sequences, including the existence of unique epigenetic marks such as trimethylation on lysine 4 of histone H3 at promoter site and trimethylation on lysine 36 of histone H3 along the transcribed region. Their sequence also possesses These authors contributed equally: Hassan Yousefi, Maryam Maheronnaghsh, Fatemeh Molae * Suresh K. Alahari salaha@lsuhsc.edu 1 Department of Biochemistry and Molecular Biology, LSUHSC, School of Medicine, New Orleans, LA, USA 2 Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran 3 Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran 4 Department of Genetics, Faculty of Science, Shahrekord University, Shahrekord, Iran 5 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA 6 Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland 1234567890();,: 1234567890();,: