title: Splicing program of human MENA produces a previously undescribed isoform associated with invasive, mesenchymal-like breast tumors.
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(11a) is 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 hMENA(11a), overexpression of hMENAΔv6 increased cell invasion, whereas overexpression of hMENA(11a) reduced the migratory and invasive ability of these cells. hMENA(11a) 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 hMENA(11a), 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 hMENA(11a). 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.
authors.affiliation: Department of Experimental Oncology,  Regina Elena National Cancer Institute, 00158 Rome,  Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Di Modugno
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Iapicca
authors.forename: Aaron
authors.initials: A
authors.lastname: Boudreau
authors.forename: Marcella
authors.initials: M
authors.lastname: Mottolese
authors.forename: Irene
authors.initials: I
authors.lastname: Terrenato
authors.forename: Letizia
authors.initials: L
authors.lastname: Perracchio
authors.forename: Russ P
authors.initials: RP
authors.lastname: Carstens
authors.forename: Angela
authors.initials: A
authors.lastname: Santoni
authors.forename: Mina J
authors.initials: MJ
authors.lastname: Bissell
authors.forename: Paola
authors.initials: P
authors.lastname: Nisticò
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D017398:Alternative Splicing / Q000235:genetics*; D015703:Antigens, CD; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D003001:Cloning, Molecular; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology*; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D010641:Phenotype; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D014162:Transfection; D014746:Vimentin / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C539364:ESRP1 protein, human; C511939:Enah protein, human; D008840:Microfilament Proteins; D020033:Protein Isoforms; D016601:RNA-Binding Proteins; D014746:Vimentin