title: CDC25A protein stability represents a previously unrecognized target of HER2 signaling in human breast cancer: implication for a potential clinical relevance in trastuzumab treatment.
abstract: The CDC25A-CDK2 pathway has been proposed as critical for the oncogenic action of human epidermal growth factor receptor 2 (HER2) in mammary epithelial cells. In particular, transgenic expression of CDC25A cooperates with HER2 in promoting mammary tumors, whereas CDC25A hemizygous loss attenuates the HER2-induced tumorigenesis penetrance. On the basis of this evidence of a synergism between HER2 and the cell cycle regulator CDC25A in a mouse model of mammary tumorigenesis, we investigated the role of CDC25A in human HER2-positive breast cancer and its possible implications in therapeutic response. HER2 status and CDC25A expression were assessed in 313 breast cancer patients and we found statistically significant correlation between HER2 and CDC25A (P = .007). Moreover, an HER2-positive breast cancer subgroup with high levels of CDC25A and very aggressive phenotype was identified (P = .005). Importantly, our in vitro studies on breast cancer cell lines showed that the HER2 inhibitor efficacy on cell growth and viability relied also on CDC25A expression and that such inhibition induces CDC25A down-regulation through phosphatidylinositol 3-kinase/protein kinase B pathway and DNA damage response activation. In line with this observation, we found a statistical significant association between CDC25A overexpression and trastuzumab-combined therapy response rate in two different HER2-positive cohorts of trastuzumab-treated patients in either metastatic or neoadjuvant setting (P = .018 for the metastatic cohort and P = .021 for the neoadjuvant cohort). Our findings highlight a link between HER2 and CDC25A that positively modulates HER2-targeted therapy response, suggesting that, in HER2-positive breast cancer patients, CDC25A overexpression affects trastuzumab sensitivity.
authors.affiliation: Pathology Unit, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Brunetto
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Ferrara
authors.forename: Francesca
authors.initials: F
authors.lastname: Rampoldi
authors.forename: Anna
authors.initials: A
authors.lastname: Talarico
authors.forename: Elena Dal
authors.initials: ED
authors.lastname: Cin
authors.forename: Greta
authors.initials: G
authors.lastname: Grassini
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Spagnuolo
authors.forename: Isabella
authors.initials: I
authors.lastname: Sassi
authors.forename: Antonella
authors.initials: A
authors.lastname: Ferro
authors.forename: Lucia Veronica
authors.initials: LV
authors.lastname: Cuorvo
authors.forename: Mattia
authors.initials: M
authors.lastname: Barbareschi
authors.forename: Sara
authors.initials: S
authors.lastname: Piccinin
authors.forename: Roberta
authors.initials: R
authors.lastname: Maestro
authors.forename: Lorenza
authors.initials: L
authors.lastname: Pecciarini
authors.forename: Claudio
authors.initials: C
authors.lastname: Doglioni
authors.forename: Maria Giulia
authors.initials: MG
authors.lastname: Cangi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011237:Predictive Value of Tests; D055550:Protein Stability; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D000068878:Trastuzumab; D020687:cdc25 Phosphatases / Q000378:metabolism*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D020687:cdc25 Phosphatases; C508053:ERBB2 protein, human; C517004:CDC25A protein, human