title: Prognostic value of a newly identified MALAT1 alternatively spliced transcript in breast cancer.
abstract: Epigenetic deregulation is considered as a new hallmark of cancer. The long non-coding RNA MALAT1 has been implicated in several cancers; however, its role in breast cancer is still little known.
  
  
  
  We used RT-PCR, in situ hybridisation, and RPPA methods to quantify (i) the full-length (FL) and an alternatively spliced variant (Δsv) of MALAT1, and (ii) a panel of transcripts and proteins involved in MALAT1 pathways, in a large series of breast tumours from patients with known clinical/pathological status and long-term outcome.
  
  
  
  MALAT1 was overexpressed in 14% (63/446) of the breast tumours. MALAT1-overexpressed tumour epithelial cells showed marked diffuse nuclear signals and numerous huge nuclear speckles. Screening of the dbEST database led to the identification of Δsv-MALAT1, a major alternatively spliced MALAT1 transcript, with a very different expression pattern compared with FL-MALAT1. This alternative Δsv-MALAT1 transcript was mainly underexpressed (18.8%) in our breast tumour series. Multivariate analysis showed that alternative Δsv-MALAT1 transcript is an independent prognostic factor. Δsv-MALAT1 expression was associated with alterations of the pre-mRNAs alternative splicing machinery, and of the Drosha-DGCR8 complex required for non-coding RNA biogenesis. Alternative Δsv-MALAT1 transcript expression was associated to YAP protein status and with an activation of the PI3K-AKT pathway.
  
  
  
  Our results reveal a complex expression pattern of various MALAT1 transcript variants in breast tumours, and suggest that this pattern of expressions should be taken into account to evaluate MALAT1 as predictive biomarker and therapeutic target.
authors.affiliation: Department of Genetics, Unit of Pharmacogenetics, Institut Curie, 26 rue d'Ulm, Paris Cedex F-75248, France.|Department of Pathology, Platform of Investigative Pathology, Institut Curie, 26 rue d'Ulm, Paris Cedex F-75248, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Meseure
authors.affiliation: Department of Genetics, Unit of Pharmacogenetics, Institut Curie, 26 rue d'Ulm, Paris Cedex F-75248, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Vacher
authors.affiliation: Department of Genetics, Unit of Pharmacogenetics, Institut Curie, 26 rue d'Ulm, Paris Cedex F-75248, France.
authors.forename: François
authors.initials: F
authors.lastname: Lallemand
authors.affiliation: Department of Pathology, Platform of Investigative Pathology, Institut Curie, 26 rue d'Ulm, Paris Cedex F-75248, France.
authors.forename: Kinan Drak
authors.initials: KD
authors.lastname: Alsibai
authors.affiliation: Department of Genetics, Unit of Pharmacogenetics, Institut Curie, 26 rue d'Ulm, Paris Cedex F-75248, France.
authors.forename: Rana
authors.initials: R
authors.lastname: Hatem
authors.affiliation: Department of Genetics, Unit of Pharmacogenetics, Institut Curie, 26 rue d'Ulm, Paris Cedex F-75248, France.
authors.forename: Walid
authors.initials: W
authors.lastname: Chemlali
authors.affiliation: Department of Pathology, Platform of Investigative Pathology, Institut Curie, 26 rue d'Ulm, Paris Cedex F-75248, France.
authors.forename: Andre
authors.initials: A
authors.lastname: Nicolas
authors.affiliation: Department of Translational Research, Institut Curie, 26 rue d'Ulm, Paris Cedex F-75248, France.
authors.forename: Leanne
authors.initials: L
authors.lastname: De Koning
authors.affiliation: EA7331, Faculty of Pharmaceutical and Biological Sciences, Paris Descartes University, Sorbonne Paris Cité, Paris Cedex F-75006, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Pasmant
authors.affiliation: Department of Genetics, Unit of Pharmacogenetics, Institut Curie, 26 rue d'Ulm, Paris Cedex F-75248, France.
authors.forename: Celine
authors.initials: C
authors.lastname: Callens
authors.affiliation: Department of Genetics, Unit of Pharmacogenetics, Institut Curie, 26 rue d'Ulm, Paris Cedex F-75248, France.
authors.forename: Rosette
authors.initials: R
authors.lastname: Lidereau
authors.affiliation: CNRS UMR 3244, Institut Curie, 26 rue d'Ulm, Paris Cedex F-75248, France.
authors.forename: Antonin
authors.initials: A
authors.lastname: Morillon
authors.affiliation: Department of Genetics, Unit of Pharmacogenetics, Institut Curie, 26 rue d'Ulm, Paris Cedex F-75248, France.|EA7331, Faculty of Pharmaceutical and Biological Sciences, Paris Descartes University, Sorbonne Paris Cité, Paris Cedex F-75006, France.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bieche
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D057890:Epigenomics; D005260:Female; D006801:Humans; D008875:Middle Aged; D011379:Prognosis; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: C561518:CDKN2B antisense RNA, human; C561566:HOTAIR long untranslated RNA, human; C557041:MALAT1 long non-coding RNA, human; D062085:RNA, Long Noncoding; D012333:RNA, Messenger