title: Topographic expression of the Hippo transducers TAZ and YAP in triple-negative breast cancer treated with neoadjuvant chemotherapy.
abstract: BACKGROUND
  The Hippo signaling acts as a tumor-suppressor pathway that negatively regulates TAZ and YAP. Increasing evidence supports the activation of TAZ and YAP in breast cancer. Moreover, the Hippo pathway is involved in the biology of non-neoplastic cells residing in the tumor microenvironment. On this basis, we herein assessed TAZ and YAP in triple-negative breast cancer and its surrounding microenvironemnt in order to investigate their impact on pathological complete response (pCR) and tumor recurrence.
  
  
  METHODS
  Sixty-one triple-negative breast cancer patients treated with neoadjuvant chemotherapy were retrospectively evaluated. TAZ and YAP were assessed by immunohistochemistry and classified as positive or negative according to the percentage of tumor-expressing cells, cellular localization, and staining intensity. TAZ and YAP expression was also evaluated in non-lymphocytic stromal cells, tumor-infiltrating lymphocytes (TILs) and endothelial cells. The Pearson's Chi-squared test of independence was used to test the association between TAZ/YAP and clinical-molecular factors. A multivariate logistic regression model was generated to identify variables impacting pCR. The Kaplan-Meier method and the log-rank test were used for estimating and comparing survival curves. Cox proportional regression models were built to evaluate the risk of recurrence for the variables considered. Internal validation was carried out with a re-sampling without replacement method.
  
  
  RESULTS
  We did not observe any impact on pCR rate when TAZ and YAP were addressed singularly. Conversely, the combined expression of YAP in tumor cells and non-lymphocytic stromal cells was an independent predictor of reduced pCR rate in the multivariate model (OR 7.13, 95% CI: 1.23-41.41, p = 0.029). Next, the combined expression of TAZ and YAP was associated with shorter disease-free survival (DFS) in multivariate analysis (HR 3.07, 95% CI: 1.24-7.61, p = 0.016). The robustness of these findings were internally validated.
  
  
  CONCLUSIONS
  The combined expression of YAP in TNBC cells and in the surrounding stroma seems to be associated with a decreased likelihood to achieve pCR. Conversely, the combined expression of TAZ and YAP in tumor cells conferred poor survival outcomes.
authors.affiliation: Division of Medical Oncology B, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Vici
authors.affiliation: Department of Pathology, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Ercolani
authors.affiliation: Department of Pathology, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Di Benedetto
authors.affiliation: Division of Medical Oncology B, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Pizzuti
authors.affiliation: Division of Medical Oncology B, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Di Lauro
authors.affiliation: Biostatistics-Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Sperati
authors.affiliation: Biostatistics-Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Terrenato
authors.affiliation: Medical Oncology Unit, ASL Frosinone, Frosinone, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Gamucci
authors.affiliation: Department of Experimental and Clinical Sciences, University "G. d'Annunzio", Chieti, Italy.
authors.forename: Clara
authors.initials: C
authors.lastname: Natoli
authors.affiliation: Department of Surgery, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Di Filippo
authors.affiliation: Department of Surgery, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Botti
authors.affiliation: Division of Medical Oncology B, "Regina Elena" National Cancer Institute, Rome, Italy.|Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Barba
authors.affiliation: Department of Pathology, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Mottolese
authors.affiliation: Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy. demaria@ifo.it.|Division of Medical Oncology B and Scientific Direction, "Regina Elena" National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy. demaria@ifo.it.
authors.forename: Ruggero
authors.initials: R
authors.lastname: De Maria
authors.affiliation: Division of Medical Oncology B, "Regina Elena" National Cancer Institute, Rome, Italy. maugeri.marcello@gmail.com.|Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy. maugeri.marcello@gmail.com.|Division of Medical Oncology B and Scientific Direction, "Regina Elena" National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy. maugeri.marcello@gmail.com.
authors.forename: Marcello
authors.initials: M
authors.lastname: Maugeri-Saccà
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D016015:Logistic Models; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods*; D010750:Phosphoproteins / Q000378:metabolism*; D012189:Retrospective Studies; D016019:Survival Analysis; D014157:Transcription Factors / Q000378:metabolism*; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D000217:Acyltransferases; C108675:TAFAZZIN protein, human
keywords: Hippo pathway; Stromal cells; TAZ; Triple-negative breast cancer; YAP