title: LIMT is a novel metastasis inhibiting lncRNA suppressed by EGF and downregulated in aggressive breast cancer.
abstract: Long noncoding RNAs (lncRNAs) are emerging as regulators of gene expression in pathogenesis, including cancer. Recently, lncRNAs have been implicated in progression of specific subtypes of breast cancer. One aggressive, basal-like subtype associates with increased EGFR signaling, while another, the HER2-enriched subtype, engages a kin of EGFR Based on the premise that EGFR-regulated lncRNAs might control the aggressiveness of basal-like tumors, we identified multiple EGFR-inducible lncRNAs in basal-like normal cells and overlaid them with the transcriptomes of over 3,000 breast cancer patients. This led to the identification of 11 prognostic lncRNAs. Functional analyses of this group uncovered LINC01089 (here renamed LncRNA Inhibiting Metastasis; LIMT), a highly conserved lncRNA, which is depleted in basal-like and in HER2-positive tumors, and the low expression of which predicts poor patient prognosis. Interestingly, EGF rapidly downregulates LIMT expression by enhancing histone deacetylation at the respective promoter. We also find that LIMT inhibits extracellular matrix invasion of mammary cells in vitro and tumor metastasis in vivo In conclusion, lncRNAs dynamically regulated by growth factors might act as novel drivers of cancer progression and serve as prognostic biomarkers.
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Aldema
authors.initials: A
authors.lastname: Sas-Chen
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Miriam R
authors.initials: MR
authors.lastname: Aure
authors.affiliation: Department of Computer Sciences, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Limor
authors.initials: L
authors.lastname: Leibovich
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Silvia
authors.initials: S
authors.lastname: Carvalho
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yehoshua
authors.identifier: 0000-0001-6327-2845
authors.initials: Y
authors.lastname: Enuka
authors.affiliation: Division of Molecular Genome Analysis, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Cindy
authors.initials: C
authors.lastname: Körner
authors.affiliation: Division of RNA Biology & Cancer (B150), German Cancer Research Center (DKFZ), Heidelberg, Germany Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Polycarpou-Schwarz
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Sara
authors.initials: S
authors.lastname: Lavi
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Nava
authors.initials: N
authors.lastname: Nevo
authors.affiliation: Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Kuznetsov
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Justin
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Department of Oncology, Luxembourg Institute of Health, Luxembourg City, Luxembourg.
authors.forename: Francisco
authors.initials: F
authors.lastname: Azuaje
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Igor
authors.initials: I
authors.lastname: Ulitsky
authors.affiliation: Division of RNA Biology & Cancer (B150), German Cancer Research Center (DKFZ), Heidelberg, Germany Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany German Cancer Consortium (DKTK), Freiburg, Germany Division of Cancer Research, Department of Thoracic Surgery, Faculty of Medicine, Medical Center - University of Freiburg, University of Freiburg, Freiburg, Germany‡
authors.forename: Sven
authors.identifier: 0000-0001-7901-4752
authors.initials: S
authors.lastname: Diederichs
authors.affiliation: Division of Molecular Genome Analysis, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wiemann
authors.affiliation: Department of Computer Sciences, Technion-Israel Institute of Technology, Haifa, Israel Agilent Laboratories, Petach-Tikva, Israel.
authors.forename: Zohar
authors.initials: Z
authors.lastname: Yakhini
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Vessela N
authors.initials: VN
authors.lastname: Kristensen
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel yosef.yarden@weizmann.ac.il.
authors.forename: Yosef
authors.identifier: 0000-0001-8578-0250
authors.initials: Y
authors.lastname: Yarden
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology*; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D062085:RNA, Long Noncoding / Q000096:biosynthesis*
chemical_list: D062085:RNA, Long Noncoding; D004815:Epidermal Growth Factor
keywords: biomarkers; breast cancer; long noncoding RNA; migration; receptor tyrosine kinase