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Genes Dev. 2016 Jan 1;30(1):34-51. doi: 10.1101/gad.270959.115. Epub 2015 Dec 23.

Differentiation of mammary tumors and reduction in metastasis upon Malat1 lncRNA loss.

Author information

1
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
2
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;
3
Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA;
4
Ionis Pharmaceuticals, Inc., Carlsbad, California 92010, USA;
5
Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.

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.

KEYWORDS:

Malat1; antisense therapy; breast cancer; metastasis; noncoding RNA; tumor differentiation; tumor organoids

PMID:
26701265
PMCID:
PMC4701977
DOI:
10.1101/gad.270959.115
[Indexed for MEDLINE]
Free PMC Article

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