TY - JOUR
T1 - LIMT is a novel metastasis inhibiting lncRNA suppressed by EGF and downregulated in aggressive breast cancer
AU - Sas-Chen, Aldema
AU - Aure, Miriam R.
AU - Leibovich, Limor
AU - Carvalho, Silvia
AU - Enuka, Yehoshua
AU - Körner, Cindy
AU - Polycarpou-Schwarz, Maria
AU - Lavi, Sara
AU - Nevo, Nava
AU - Kuznetsov, Yuri
AU - Yuan, Justin
AU - Azuaje, Francisco
AU - Ulitsky, Igor
AU - Diederichs, Sven
AU - Wiemann, Stefan
AU - Yakhini, Zohar
AU - Kristensen, Vessela N.
AU - Børresen-Dale, Anne Lise
AU - Yarden, Yosef
AU - Sauer, Torill
AU - Geisler, Jürgen
AU - Hofvind, Solveig
AU - Bathen, Tone F.
AU - Borgen, Elin
AU - Engebråten, Olav
AU - Fodstad, Øystein
AU - Garred, Øystein
AU - Geitvik, Gry Aarum
AU - Kåresen, Rolf
AU - Naume, Bjørn
AU - Mælandsmo, Gunhild Mari
AU - Russnes, Hege G.
AU - Schlichting, Ellen
AU - Sørlie, Therese
AU - Lingjærde, Ole Christian
AU - Sahlberg, Kristine Kleivi
AU - Skjerven, Helle Kristine
AU - Fritzman, Britt
AU - Oslo Breast Cancer Research Consortium (OSBREAC)
N1 - Funding Information:
We thank members of our groups for support and help. We thank Dr. Swati Srivastava for her creative contribution. Our research is supported by the U.S. National Cancer Institute (Grant 5R37CA072981), the European Research Council, the Seventh Framework Program of the European Commission, the German-Israeli Project Cooperation (DIP), the Israel Cancer Research Fund, the Rising Tide Foundation, the Israel Science Foundation (ISF), and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. Y.Y. is the incumbent of the Harold and Zelda Goldenberg Professorial Chair in Molecular Cell Biology. L.L. was partially supported by Israel Ministry of Science and Technology and by an ISEF Fellowship. M.R.A was a postdoctoral fellow of the South-Eastern Norway Regional Health Authority (grant 368039-6051-39648). Research in the Diederichs laboratory is supported by the German Research Foundation (DFG Transregio TRR77, Di 1421/7-1), the Excellence Cluster CellNetworks, the Helmholtz Society, the Virtual Helmholtz Institute for Resistance in Leukemia and the European Union (Marie Curie Grant).
Publisher Copyright:
© 2016 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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.
AB - 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.
KW - biomarkers
KW - breast cancer
KW - long noncoding RNA
KW - migration
KW - receptor tyrosine kinase
UR - http://www.scopus.com/inward/record.url?scp=84984791967&partnerID=8YFLogxK
U2 - 10.15252/emmm.201606198
DO - 10.15252/emmm.201606198
M3 - Article
C2 - 27485121
AN - SCOPUS:84984791967
SN - 1757-4676
VL - 8
SP - 1052
EP - 1064
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 9
ER -