title: ATM kinase sustains HER2 tumorigenicity in breast cancer.
abstract: ATM kinase preserves genomic stability by acting as a tumour suppressor. However, its identification as a component of several signalling networks suggests a dualism for ATM in cancer. Here we report that ATM expression and activity promotes HER2-dependent tumorigenicity in vitro and in vivo. We reveal a correlation between ATM activation and the reduced time to recurrence in patients diagnosed with invasive HER2-positive breast cancer. Furthermore, we identify ATM as a novel modulator of HER2 protein stability that acts by promoting a complex of HER2 with the chaperone HSP90, therefore preventing HER2 ubiquitination and degradation. As a consequence, ATM sustains AKT activation downstream of HER2 and may modulate the response to therapeutic approaches, suggesting that the status of ATM activity may be informative for the treatment and prognosis of HER2-positive tumours. Our findings provide evidence for ATM's tumorigenic potential revising the canonical role of ATM as a pure tumour suppressor.
authors.affiliation: 1] Laboratory of Cell Signaling, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, 00179 Rome, Italy [2] Department of Biology, University of Rome 'Tor Vergata', 00133 Rome, Italy.
authors.forename: Venturina
authors.initials: V
authors.lastname: Stagni
authors.affiliation: Experimental Oncology, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Manni
authors.affiliation: 1] Laboratory of Cell Signaling, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, 00179 Rome, Italy [2] Department of Biology, University of Rome 'Tor Vergata', 00133 Rome, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Oropallo
authors.affiliation: Department of Pathology, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Mottolese
authors.affiliation: Department of Pathology, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Di Benedetto
authors.affiliation: Experimental Oncology, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Giulia
authors.identifier: 0000000321141892
authors.initials: G
authors.lastname: Piaggio
authors.affiliation: Experimental Oncology, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Falcioni
authors.affiliation: 1] Laboratory of Cell Signaling, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, 00179 Rome, Italy [2] Department of Biology, University of Rome 'Tor Vergata', 00133 Rome, Italy.
authors.forename: Danilo
authors.initials: D
authors.lastname: Giaccari
authors.affiliation: Experimental Oncology, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Selene
authors.initials: S
authors.lastname: Di Carlo
authors.affiliation: Biostatistic Unit, Scientific Direction, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Sperati
authors.affiliation: Laboratory of Neuroimmunology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, 00179 Rome, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Cencioni
authors.affiliation: 1] Laboratory of Cell Signaling, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, 00179 Rome, Italy [2] Department of Biology, University of Rome 'Tor Vergata', 00133 Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Barilà
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D005260:Female; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D061986:MCF-7 Cells; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009368:Neoplasm Transplantation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D018841:HSP90 Heat-Shock Proteins; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C576324:ATM protein, human