title: Expression of phosphorylated Hippo pathway kinases (MST1/2 and LATS1/2) in HER2-positive and triple-negative breast cancer patients treated with neoadjuvant therapy.
abstract: The Hippo kinases MST1/2 and LATS1/2 inhibit the oncoproteins TAZ/YAP and regulate T cell function. Hippo kinases also cooperate with the ATR-Chk1 and ATM-Chk2 pathways, central orchestrators of the DNA damage response (DDR). We hypothesized that MST1/2 and LATS1/2 localization differently impacts the efficacy of neoadjuvant therapy (NAT) in breast cancer, being protective when expressed in the cytoplasm of tumor cells and in tumor-infiltrating lymphocytes, whereas representing molecular determinants of chemoresistance when present in the nucleus as a consequence of their cooperation with the DDR. Diagnostic biopsies from 57 HER2-positive and triple-negative breast cancer patients treated with NAT were immunostained for evaluating the expression of phosphorylated MST1/2 (pMST1/2) and LATS1/2 (pLATS1/2) in tumor-infiltrating lymphocytes (TILs) and in cancer cells. TAZ and Chk1 immunostaining was exploited for investigating subcellular compartment-dependent activity of Hippo kinases. Nuclear pMST1/2 (pMST1/2nuc) expression was significantly associated with nuclear expression of Chk1 (p = 0.046), whereas cytoplasmic pMST1/2 (pMST1/2cyt) expression was marginally associated with cytoplasmic TAZ staining (p = 0.053). Patients whose tumors expressed pMST1/2nucwere at increased risk of residual disease after NAT (pCR ypT0/is ypN0: OR 4.91, 95%CI: 1.57-15.30; pCR ypT0 ypN0: OR 3.59, 95%CI 1.14-11.34). Conversely, exclusive cytoplasmic localization of pMST1/2 (pMST1/2cyt)seemed to be a protective factor (pCR ypT0/is ypN0: OR 0.34, 95%CI: 0.11-1.00; pCR ypT0 ypN0: OR 0.31, 95%CI 0.10-0.93). The subcellular localization-dependent significance of pMST1/2 expression suggests their involvement in different molecular networks with opposite impact on NAT efficacy. Larger studies are warranted to confirm these novel findings.
authors.affiliation: a Department of Pathology , "Regina Elena" National Cancer Institute, Via Elio Chianesi , Rome , Italy.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Ercolani
authors.affiliation: a Department of Pathology , "Regina Elena" National Cancer Institute, Via Elio Chianesi , Rome , Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Di Benedetto
authors.affiliation: b Biostatistics-Scientific Direction , "Regina Elena" National Cancer Institute , Via Elio Chianes, Rome , Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Terrenato
authors.affiliation: c Division of Medical Oncology 2 , "Regina Elena" National Cancer Institute , Via Elio Chianesi, Rome , Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Pizzuti
authors.affiliation: c Division of Medical Oncology 2 , "Regina Elena" National Cancer Institute , Via Elio Chianesi, Rome , Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Di Lauro
authors.affiliation: c Division of Medical Oncology 2 , "Regina Elena" National Cancer Institute , Via Elio Chianesi, Rome , Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Sergi
authors.affiliation: b Biostatistics-Scientific Direction , "Regina Elena" National Cancer Institute , Via Elio Chianes, Rome , Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Sperati
authors.affiliation: a Department of Pathology , "Regina Elena" National Cancer Institute, Via Elio Chianesi , Rome , Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Buglioni
authors.affiliation: d Division of Pathology, ASL Frosinone , Via Armando Fabi, Frosinone , Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Ramieri
authors.affiliation: e Medical Oncology Unit, ASL Frosinone , Frosinone, Via Armando Fabi , Frosinone , Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Mentuccia
authors.affiliation: e Medical Oncology Unit, ASL Frosinone , Frosinone, Via Armando Fabi , Frosinone , Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Gamucci
authors.affiliation: a Department of Pathology , "Regina Elena" National Cancer Institute, Via Elio Chianesi , Rome , Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Perracchio
authors.affiliation: a Department of Pathology , "Regina Elena" National Cancer Institute, Via Elio Chianesi , Rome , Italy.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Pescarmona
authors.affiliation: a Department of Pathology , "Regina Elena" National Cancer Institute, Via Elio Chianesi , Rome , Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Mottolese
authors.affiliation: c Division of Medical Oncology 2 , "Regina Elena" National Cancer Institute , Via Elio Chianesi, Rome , Italy.|f Scientific Direction , "Regina Elena" National Cancer Institute, Via Elio Chianesi , Rome , Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Barba
authors.affiliation: c Division of Medical Oncology 2 , "Regina Elena" National Cancer Institute , Via Elio Chianesi, Rome , Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Vici
authors.affiliation: g Institute of General Pathology, Catholic University of the Sacred Heart, Largo Agostino Gemelli , Rome , Italy.
authors.forename: Ruggero
authors.initials: R
authors.lastname: De Maria
authors.affiliation: c Division of Medical Oncology 2 , "Regina Elena" National Cancer Institute , Via Elio Chianesi, Rome , Italy.|f Scientific Direction , "Regina Elena" National Cancer Institute, Via Elio Chianesi , Rome , Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Maugeri-Saccà
mesh_terms: D000328:Adult; D000368:Aged; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000473:pathology; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D017228:Hepatocyte Growth Factor; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C082332:macrophage stimulating protein; C092745:LATS1 protein, human; C508053:ERBB2 protein, human
keywords: HER2-positive breast cancer; Hippo pathway; LATS 1/2; MST1/2; triple-negative breast cancer