title: Primate-specific oestrogen-responsive long non-coding RNAs regulate proliferation and viability of human breast cancer cells.
abstract: Long non-coding RNAs (lncRNAs) are transcripts of a recently discovered class of genes which do not code for proteins. LncRNA genes are approximately as numerous as protein-coding genes in the human genome. However, comparatively little remains known about lncRNA functions. We globally interrogated changes in the lncRNA transcriptome of oestrogen receptor positive human breast cancer cells following treatment with oestrogen, and identified 127 oestrogen-responsive lncRNAs. Consistent with the emerging evidence that most human lncRNA genes lack homologues outside of primates, our evolutionary analysis revealed primate-specific lncRNAs downstream of oestrogen signalling. We demonstrate, using multiple functional assays to probe gain- and loss-of-function phenotypes in two oestrogen receptor positive human breast cancer cell lines, that two primate-specific oestrogen-responsive lncRNAs identified in this study (the oestrogen-repressed lncRNA BC041455, which reduces cell viability, and the oestrogen-induced lncRNA CR593775, which increases cell viability) exert previously unrecognized functions in cell proliferation and growth factor signalling pathways. The results suggest that oestrogen-responsive lncRNAs are capable of altering the proliferation and viability of human breast cancer cells. No effects on cellular phenotypes were associated with control transfections. As heretofore unappreciated components of key signalling pathways in cancers, including the MAP kinase pathway, lncRNAs hence represent a novel mechanism of action for oestrogen effects on cellular proliferation and viability phenotypes. This finding warrants further investigation in basic and translational studies of breast and potentially other types of cancers, has broad relevance to lncRNAs in other nuclear hormone receptor pathways, and should facilitate exploiting and targeting these cell viability modulating lncRNAs in post-genomic therapeutics.
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77004, USA.
authors.forename: Chin-Yo
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Erica L
authors.identifier: 0000-0002-8565-207X
authors.initials: EL
authors.lastname: Kleinbrink
authors.affiliation: Department of Neurology, School of Medicine, Wayne State University, Detroit, MI 48201, USA.|Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA.|Department of Neurology and Rehabilitation, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Fabien
authors.initials: F
authors.lastname: Dachet
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Cai
authors.affiliation: Department of Surgery and Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Donghong
authors.initials: D
authors.lastname: Ju
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Goldstone
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Wood
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77004, USA.
authors.forename: Ka
authors.initials: K
authors.lastname: Liu
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Jia
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Anton-Scott
authors.identifier: 0000-0002-4483-5101
authors.initials: AS
authors.lastname: Goustin
authors.affiliation: Department of Surgery and Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Kosir
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Pattaraporn
authors.initials: P
authors.lastname: Thepsuwan
authors.affiliation: Department of Neurology, School of Medicine, Wayne State University, Detroit, MI 48201, USA llipovich@med.wayne.edu.|Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Leonard
authors.identifier: 0000-0002-0531-3570
authors.initials: L
authors.lastname: Lipovich
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003001:Cloning, Molecular; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011323:Primates / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000235:genetics*
chemical_list: D004967:Estrogens; D062085:RNA, Long Noncoding; C000624534:long non-coding RNA CR593775, human; C000624533:long non-coding RNA LINC01671, human
keywords: MAP kinase; cancer; evolution; long non-coding RNA; oestrogen