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J Exp Clin Cancer Res. 2016 Apr 2;35:62. doi: 10.1186/s13046-016-0338-7.

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

Author information

  • 1Division of Medical Oncology B, "Regina Elena" National Cancer Institute, Rome, Italy.
  • 2Department of Pathology, "Regina Elena" National Cancer Institute, Rome, Italy.
  • 3Biostatistics-Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy.
  • 4Medical Oncology Unit, ASL Frosinone, Frosinone, Italy.
  • 5Department of Experimental and Clinical Sciences, University "G. d'Annunzio", Chieti, Italy.
  • 6Department of Surgery, "Regina Elena" National Cancer Institute, Rome, Italy.
  • 7Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy.
  • 8Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy. demaria@ifo.it.
  • 9Division of Medical Oncology B and Scientific Direction, "Regina Elena" National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy. demaria@ifo.it.
  • 10Division of Medical Oncology B, "Regina Elena" National Cancer Institute, Rome, Italy. maugeri.marcello@gmail.com.
  • 11Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy. maugeri.marcello@gmail.com.
  • 12Division of Medical Oncology B and Scientific Direction, "Regina Elena" National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy. maugeri.marcello@gmail.com.

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.

KEYWORDS:

Hippo pathway; Stromal cells; TAZ; Triple-negative breast cancer; YAP

PMID:
27039292
PMCID:
PMC4818869
DOI:
10.1186/s13046-016-0338-7
[PubMed - indexed for MEDLINE]
Free PMC Article
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