Functional and prognostic significance of long non-coding RNA MALAT1 as a metastasis driver in ER negative lymph node negative breast cancer

Mahdieh Jadaliha, Xinying Zong, Pushkar Malakar, Tania Ray, Deepak K. Singh, Susan M. Freier, Tor Jensen, Supriya G. Prasanth, Rotem Karni, Partha S. Ray, Kannanganattu V. Prasanth

Research output: Contribution to journalArticle

Abstract

MALAT1 (metastasis associated lung adenocarcinoma transcript1) is a conserved long non-coding RNA, known to regulate gene expression by modulating transcription and post-transcriptional pre-mRNA processing of a large number of genes. MALAT1 expression is deregulated in various tumors, including breast cancer. However, the significance of such abnormal expression is yet to be fully understood. In this study, we demonstrate that regulation of aggressive breast cancer cell traits by MALAT1 is not predicted solely based on an elevated expression level but is context specific. By performing loss- and gain-of-function studies, both under in vitro and in vivo conditions, we demonstrate that MALAT1 facilitates cell proliferation, tumor progression and metastasis of triple-negative breast cancer (TNBC) cells despite having a comparatively lower expression level than ER or HER2-positive breast cancer cells. Furthermore, MALAT1 regulates the expression of several cancer metastasis-related genes, but displays molecular subtype specific correlations with such genes. Assessment of the prognostic significance of MALAT1 in human breast cancer (n=1992) revealed elevated MALAT1 expression was associated with decreased disease-specific survival in ER negative, lymph node negative patients of the HER2 and TNBC molecular subtypes. Multivariable analysis confirmed MALAT1 to have independent prognostic significance in the TNBC lymph node negative patient subset (HR=2.64, 95%CI 1.35- 5.16, p=0.005). We propose that the functional significance of MALAT1 as a metastasis driver and its potential use as a prognostic marker is most promising for those patients diagnosed with ER negative, lymph node negative breast cancer who might otherwise mistakenly be stratified to have low recurrence risk.

Original languageEnglish (US)
Pages (from-to)40418-40436
Number of pages19
JournalOncotarget
Volume7
Issue number26
DOIs
StatePublished - Jan 1 2016

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Long Noncoding RNA
Lymph Nodes
Breast Neoplasms
Neoplasm Metastasis
Triple Negative Breast Neoplasms
Adenocarcinoma of lung
Genes
Neoplasms
RNA Precursors

Keywords

  • Basal-like breast cancer cells
  • Breast cancer
  • IncRNA
  • Nuclear speckle
  • Triple negative breast cancer

ASJC Scopus subject areas

  • Oncology

Cite this

Functional and prognostic significance of long non-coding RNA MALAT1 as a metastasis driver in ER negative lymph node negative breast cancer. / Jadaliha, Mahdieh; Zong, Xinying; Malakar, Pushkar; Ray, Tania; Singh, Deepak K.; Freier, Susan M.; Jensen, Tor; Prasanth, Supriya G.; Karni, Rotem; Ray, Partha S.; Prasanth, Kannanganattu V.

In: Oncotarget, Vol. 7, No. 26, 01.01.2016, p. 40418-40436.

Research output: Contribution to journalArticle

Jadaliha, Mahdieh ; Zong, Xinying ; Malakar, Pushkar ; Ray, Tania ; Singh, Deepak K. ; Freier, Susan M. ; Jensen, Tor ; Prasanth, Supriya G. ; Karni, Rotem ; Ray, Partha S. ; Prasanth, Kannanganattu V. / Functional and prognostic significance of long non-coding RNA MALAT1 as a metastasis driver in ER negative lymph node negative breast cancer. In: Oncotarget. 2016 ; Vol. 7, No. 26. pp. 40418-40436.
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AU - Jadaliha, Mahdieh

AU - Zong, Xinying

AU - Malakar, Pushkar

AU - Ray, Tania

AU - Singh, Deepak K.

AU - Freier, Susan M.

AU - Jensen, Tor

AU - Prasanth, Supriya G.

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AU - Prasanth, Kannanganattu V.

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AB - MALAT1 (metastasis associated lung adenocarcinoma transcript1) is a conserved long non-coding RNA, known to regulate gene expression by modulating transcription and post-transcriptional pre-mRNA processing of a large number of genes. MALAT1 expression is deregulated in various tumors, including breast cancer. However, the significance of such abnormal expression is yet to be fully understood. In this study, we demonstrate that regulation of aggressive breast cancer cell traits by MALAT1 is not predicted solely based on an elevated expression level but is context specific. By performing loss- and gain-of-function studies, both under in vitro and in vivo conditions, we demonstrate that MALAT1 facilitates cell proliferation, tumor progression and metastasis of triple-negative breast cancer (TNBC) cells despite having a comparatively lower expression level than ER or HER2-positive breast cancer cells. Furthermore, MALAT1 regulates the expression of several cancer metastasis-related genes, but displays molecular subtype specific correlations with such genes. Assessment of the prognostic significance of MALAT1 in human breast cancer (n=1992) revealed elevated MALAT1 expression was associated with decreased disease-specific survival in ER negative, lymph node negative patients of the HER2 and TNBC molecular subtypes. Multivariable analysis confirmed MALAT1 to have independent prognostic significance in the TNBC lymph node negative patient subset (HR=2.64, 95%CI 1.35- 5.16, p=0.005). We propose that the functional significance of MALAT1 as a metastasis driver and its potential use as a prognostic marker is most promising for those patients diagnosed with ER negative, lymph node negative breast cancer who might otherwise mistakenly be stratified to have low recurrence risk.

KW - Basal-like breast cancer cells

KW - Breast cancer

KW - IncRNA

KW - Nuclear speckle

KW - Triple negative breast cancer

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