title: hMENA(11a) contributes to HER3-mediated resistance to PI3K inhibitors in HER2-overexpressing breast cancer cells.
abstract: Human Mena (hMENA), an actin regulatory protein of the ENA/VASP family, cooperates with ErbB receptor family signaling in breast cancer. It is overexpressed in high-risk preneoplastic lesions and in primary breast tumors where it correlates with HER2 overexpression and an activated status of AKT and MAPK. The concomitant overexpression of hMENA and HER2 in breast cancer patients is indicative of a worse prognosis. hMENA is expressed along with alternatively expressed isoforms, hMENA(11a) and hMENAΔv6 with opposite functions. A novel role for the epithelial-associated hMENA(11a) isoform in sustaining HER3 activation and pro-survival pathways in HER2-overexpressing breast cancer cells has been identified by reverse phase protein array and validated in vivo in a series of breast cancer tissues. As HER3 activation is crucial in mechanisms of cell resistance to PI3K inhibitors, we explored whether hMENA(11a) is involved in these resistance mechanisms. The specific hMENA(11a) depletion switched off the HER3-related pathway activated by PI3K inhibitors and impaired the nuclear accumulation of HER3 transcription factor FOXO3a induced by PI3K inhibitors, whereas PI3K inhibitors activated hMENA(11a) phosphorylation and affected its localization. At the functional level, we found that hMENA(11a) sustains cell proliferation and survival in response to PI3K inhibitor treatment, whereas hMENA(11a) silencing increases molecules involved in cancer cell apoptosis. As shown in three-dimensional cultures, hMENA(11a) contributes to resistance to PI3K inhibition because its depletion drastically reduced cell viability upon treatment with PI3K inhibitor BEZ235. Altogether, these results indicate that hMENA(11a) in HER2-overexpressing breast cancer cells sustains HER3/AKT axis activation and contributes to HER3-mediated resistance mechanisms to PI3K inhibitors. Thus, hMENA(11a) expression can be proposed as a marker of HER3 activation and resistance to PI3K inhibition therapies, to select patients who may benefit from these combined targeted treatments. hMENA(11a) activity could represent a new target for antiproliferative therapies in breast cancer.
authors.affiliation: Laboratory of Immunology, Experimental Oncology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Trono
authors.affiliation: Laboratory of Immunology, Experimental Oncology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Di Modugno
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Circo
authors.affiliation: Laboratory of Immunology, Experimental Oncology, Regina Elena National Cancer Institute, Rome, Italy.|Department of Molecular Medicine, Sapienza, University of Rome, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Spada
authors.affiliation: Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Di Benedetto
authors.affiliation: Laboratory of Immunology, Experimental Oncology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Melchionna
authors.affiliation: Laboratory of Immunology, Experimental Oncology, Regina Elena National Cancer Institute, Rome, Italy.|Department of Molecular Medicine, Sapienza, University of Rome, Rome, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Palermo
authors.affiliation: Experimental Oncology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Matteoni
authors.affiliation: Experimental Oncology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Soddu
authors.affiliation: Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Mottolese
authors.affiliation: Scientific Direction, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: De Maria
authors.affiliation: Laboratory of Immunology, Experimental Oncology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Nisticò
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D020893:Receptor, ErbB-3 / Q000235:genetics*; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D008840:Microfilament Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C511939:Enah protein, human; C581292:ERBB3 protein, human