title: The cooperation between hMena overexpression and HER2 signalling in breast cancer.
abstract: hMena and the epithelial specific isoform hMena(11a) are actin cytoskeleton regulatory proteins belonging to the Ena/VASP family. EGF treatment of breast cancer cell lines upregulates hMena/hMena(11a) expression and phosphorylates hMena(11a), suggesting cross-talk between the ErbB receptor family and hMena/hMena(11a) in breast cancer. The aim of this study was to determine whether the hMena/hMena(11a) overexpression cooperates with HER-2 signalling, thereby affecting the HER2 mitogenic activity in breast cancer. In a cohort of breast cancer tissue samples a significant correlation among hMena, HER2 overexpression, the proliferation index (high Ki67), and phosphorylated MAPK and AKT was found and among the molecular subtypes the highest frequency of hMena overexpressing tumors was found in the HER2 subtype. From a clinical viewpoint, concomitant overexpression of HER2 and hMena identifies a subgroup of breast cancer patients showing the worst prognosis, indicating that hMena overexpression adds prognostic information to HER2 overexpressing tumors. To identify a functional link between HER2 and hMena, we show here that HER2 transfection in MCF7 cells increased hMena/hMena(11a) expression and hMena(11a) phosphorylation. On the other hand, hMena/hMena(11a) knock-down reduced HER3, AKT and p44/42 MAPK phosphorylation and inhibited the EGF and NRG1-dependent HER2 phosphorylation and cell proliferation. Of functional significance, hMena/hMena(11a) knock-down reduced the mitogenic activity of EGF and NRG1. Collectively these data provide new insights into the relevance of hMena and hMena(11a) as downstream effectors of the ErbB receptor family which may represent a novel prognostic indicator in breast cancer progression, helping to stratify patients.
authors.affiliation: Experimental Chemotherapy, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Di Modugno
authors.forename: Marcella
authors.initials: M
authors.lastname: Mottolese
authors.forename: Lucia
authors.initials: L
authors.lastname: DeMonte
authors.forename: Paola
authors.initials: P
authors.lastname: Trono
authors.forename: Michele
authors.initials: M
authors.lastname: Balsamo
authors.forename: Andrea
authors.initials: A
authors.lastname: Conidi
authors.forename: Elisa
authors.initials: E
authors.lastname: Melucci
authors.forename: Irene
authors.initials: I
authors.lastname: Terrenato
authors.forename: Francesca
authors.initials: F
authors.lastname: Belleudi
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Torrisi
authors.forename: Massimo
authors.initials: M
authors.lastname: Alessio
authors.forename: Angela
authors.initials: A
authors.lastname: Santoni
authors.forename: Paola
authors.initials: P
authors.lastname: Nisticò
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D020935:MAP Kinase Signaling System; D008840:Microfilament Proteins / Q000378:metabolism*; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D008840:Microfilament Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C511939:Enah protein, human