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

Arun, G., Diermeier, S., Akerman, M., Chang, K. C., Wilkinson, J. E., Hearn, S., Kim, Y., MacLeod, A. R., Krainer, A. R., Norton, L., Brogi, E., Egeblad, M., Spector, D. L. (2016) Differentiation of mammary tumors and reduction in metastasis upon Malat1 lncRNA loss. Genes Dev, 30 (1). pp. 34-51. ISSN 1549-5477 (Electronic)0890-9369 (Linking)

URL: http://www.ncbi.nlm.nih.gov/pubmed/26701265
DOI: 10.1101/gad.270959.115

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.

Item Type: Paper
Uncontrolled Keywords: Malat1 antisense therapy breast cancer metastasis noncoding RNA tumor differentiation tumor organoids
Subjects: diseases & disorders > cancer > cancer types > breast cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > long non-coding RNA
diseases & disorders > cancer > metastasis
CSHL Authors:
Communities: CSHL labs > Egeblad lab
CSHL labs > Krainer lab
CSHL labs > Spector lab
Highlight: Spector, David L.
Depositing User: Matt Covey
Date Deposited: 05 Jan 2016 20:34
Last Modified: 07 Sep 2017 14:24
PMCID: PMC4701977
Related URLs:
Dataset ID:
URI: http://repository.cshl.edu/id/eprint/32206

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