Topographic expression of the Hippo transducers TAZ and YAP in triple-negative breast cancer treated with neoadjuvant chemotherapy

Ruggero De Maria Marchiano, Teresa Gamucci, Patrizia Vici, Cristiana Ercolani, Anna Di Benedetto, Laura Pizzuti, Luigi Di Lauro, Francesca Sperati, Irene Terrenato, Clara Natoli, Franco Di Filippo, Claudio Botti, Maddalena Barba, Marcella Mottolese, Marcello Maugeri-Saccà

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

17 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)62-69
Numero di pagine8
RivistaJOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
Volume35
DOI
Stato di pubblicazionePubblicato - 2016

Keywords

  • Adaptor Proteins, Signal Transducing
  • Adult
  • Aged
  • Antineoplastic Agents
  • Cancer Research
  • Female
  • Hippo pathway
  • Humans
  • Logistic Models
  • Middle Aged
  • Neoadjuvant Therapy
  • Oncology
  • Phosphoproteins
  • Retrospective Studies
  • Stromal cells
  • Survival Analysis
  • TAZ
  • Transcription Factors
  • Treatment Outcome
  • Triple Negative Breast Neoplasms
  • Triple-negative breast cancer
  • YAP

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