title: Differentiation of mammary tumors and reduction in metastasis upon Malat1 lncRNA loss.
abstract: Genome-wide analyses have identified thousands of long noncoding RNAs (lncRNAs). Malat1 (metastasis-associated lung adenocarcinoma transcript 1) is among the most abundant lncRNAs whose expression is altered in numerous cancers. Here we report that genetic loss or systemic knockdown of Malat1 using antisense oligonucleotides (ASOs) in the MMTV (mouse mammary tumor virus)-PyMT mouse mammary carcinoma model results in slower tumor growth accompanied by significant differentiation into cystic tumors and a reduction in metastasis. Furthermore, Malat1 loss results in a reduction of branching morphogenesis in MMTV-PyMT- and Her2/neu-amplified tumor organoids, increased cell adhesion, and loss of migration. At the molecular level, Malat1 knockdown results in alterations in gene expression and changes in splicing patterns of genes involved in differentiation and protumorigenic signaling pathways. Together, these data demonstrate for the first time a functional role of Malat1 in regulating critical processes in mammary cancer pathogenesis. Thus, Malat1 represents an exciting therapeutic target, and Malat1 ASOs represent a potential therapy for inhibiting breast cancer progression.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
authors.forename: Gayatri
authors.initials: G
authors.lastname: Arun
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
authors.forename: Sarah
authors.initials: S
authors.lastname: Diermeier
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
authors.forename: Martin
authors.initials: M
authors.lastname: Akerman
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA; Molecular and Cellular Biology Program, Stony Brook University, Stony Brook, New York 11790, USA;
authors.forename: Kung-Chi
authors.initials: KC
authors.lastname: Chang
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA;
authors.forename: J Erby
authors.initials: JE
authors.lastname: Wilkinson
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
authors.forename: Stephen
authors.initials: S
authors.lastname: Hearn
authors.affiliation: Ionis Pharmaceuticals, Inc., Carlsbad, California 92010, USA;
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Ionis Pharmaceuticals, Inc., Carlsbad, California 92010, USA;
authors.forename: A Robert
authors.initials: AR
authors.lastname: MacLeod
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA; Molecular and Cellular Biology Program, Stony Brook University, Stony Brook, New York 11790, USA;
authors.forename: Adrian R
authors.initials: AR
authors.lastname: Krainer
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Larry
authors.initials: L
authors.lastname: Norton
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Edi
authors.initials: E
authors.lastname: Brogi
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
authors.forename: Mikala
authors.initials: M
authors.lastname: Egeblad
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA; Molecular and Cellular Biology Program, Stony Brook University, Stony Brook, New York 11790, USA;
authors.forename: David L
authors.initials: DL
authors.lastname: Spector
mesh_terms: D000818:Animals; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000503:physiopathology*; D002448:Cell Adhesion / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D009024:Morphogenesis / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics; D019154:Protein Splicing / Q000235:genetics; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: C557040:Malat1 long non-coding RNA, mouse; D062085:RNA, Long Noncoding
keywords: Malat1; antisense therapy; breast cancer; metastasis; noncoding RNA; tumor differentiation; tumor organoids