Splicing program of human MENA produces a previously undescribed isoform associated with invasive, mesenchymal-like breast tumors

Francesca Di Modugno, Pierluigi Iapicca, Aaron Boudreau, Marcella Mottolese, Irene Terrenato, Letizia Perracchio, Russ P. Carstens, Angela Santoni, Mina J. Bissell, Paola Nisticò

Research output: Contribution to journalArticle

Abstract

Human mena (hMENA), a member of the actin cytoskeleton regulators Ena/VASP, is overexpressed in high-risk preneoplastic lesions and in primary breast tumors and has been identified as playing a role in invasiveness and poor prognosis in breast cancers that express HER2. Here we identify a unique isoform, hMENAΔv6, derived from the hMENA alternative splicing program. In an isogenic model of human breast cancer progression, we show that hMENA 11ais expressed in premalignant cells, whereas hMENAΔv6 expression is restricted to invasive cancer cells. "Reversion" of the malignant phenotype leads to concurrent down-regulation of all hMENA isoforms. In breast cancer cell lines, isoform-specific hMENA overexpression or knockdown revealed that in the absence of hMENA11a, overexpression of hMENAΔv6 increased cell invasion, whereas overexpression of hMENA 11a reduced the migratory and invasive ability of these cells. hMENA11a splicing was shown to be dependent on the epithelial regulator of splicing 1 (ESRP1), and forced expression of ESRP1 in invasive mesenchymal breast cancer cells caused a phenotypic switch reminiscent of a mesenchymal-to-epithelial transition (MET) characterized by changes in the cytoskeletal architecture, reexpression of hMENA11a, and a reduction in cell invasion. hMENA-positive primary breast tumors, which are hMENA 11a-negative, are more frequently E-cadherin low in comparison with tumors expressing hMENA11a. These data suggest that polarized and growth-arrested cellular architecture correlates with absence of alternative hMENA isoform expression, and that the hMENA splicing program is relevant to malignant progression in invasive disease.

Original languageEnglish
Pages (from-to)19280-19285
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number47
DOIs
Publication statusPublished - Nov 20 2012

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Keywords

  • EMT
  • ENAH
  • Splice variants

ASJC Scopus subject areas

  • General

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