Abstract
BackgroundYes-associated protein 1 (YAP1) is a transcription factor regulated by the Hippo pathway and functions as an oncogene in various solid tumors under dysregulated Hippo pathway. However, the role of YAP1 in breast cancer remains controversial. Here, we investigated the impact of different levels of nuclear YAP1 expression on the clinical characteristics and survival outcome in patients with breast cancer.Patients and MethodsRetrospectively obtained 455 breast tumor samples at Gangnam Severance Hospital were examined for YAP1 expression by immunohistochemistry, and the clinical data were analyzed. External validation was performed using a retrospective cohort and tissues in 482 patients from Severance Hospital.ResultsHigh nuclear YAP1 expression was associated with hormone receptor negativity and aggressive tumor behavior, including lymph node metastasis, high Ki67 labeling index and inferior distant metastasis-free survival (DMFS, hazard ratio [HR] 2.271, 95% confidence intervals [CIs] 1.109–4.650, P = 0.0249), and also confirmed inferior disease free survival (HR 3.208, 95% CIs 1.313–7.833, P = 0.0105) in external validation cohort. In patients with triple-negative breast cancer (TNBC), high nuclear YAP1 expression was an independent significant determinant of poor DMFS (HR 2.384, 95% CIs 1.055–5.386, P = 0.0367).ConclusionOur findings suggest that nuclear YAP1 expression is a biomarker of adverse prognosis and a potential therapeutic target in patients with breast cancer, especially in TNBC.
Highlights
Yes-associated protein 1 (YAP1) is a transcription factor regulated by the Hippo pathway and functions as an oncogene in various solid tumors under dysregulated Hippo pathway
High nuclear YAP1 expression was associated with hormone receptor negativity and aggressive tumor behavior, including lymph node metastasis, high Ki67 labeling index and inferior distant metastasis-free survival (DMFS, hazard ratio [HR] 2.271, 95% confidence intervals [CIs] 1.109–4.650, P = 0.0249), and confirmed inferior disease free survival (HR 3.208, 95% CIs 1.313–7.833, P = 0.0105) in external validation cohort
In patients with triple-negative breast cancer (TNBC), high nuclear YAP1 expression was an independent significant determinant of poor Distant metastasis-free survival (DMFS) (HR 2.384, 95% CIs 1.055–5.386, P = 0.0367)
Summary
Yes-associated protein 1 (YAP1) is a transcription factor regulated by the Hippo pathway and functions as an oncogene in various solid tumors under dysregulated Hippo pathway. It has been reported that the transcriptional coactivator, Yes-associated protein 1 (YAP1), plays an important role in lymph node metastasis [9]. Dysregulated Hippo signaling results in the nuclear accumulation of non-phosphorylated YAP1 and TAZ These interact with transcriptional enhanced associated domain (TEAD)-containing transcription factors in nucleus, promoting the expression of genes related to cell proliferation and epithelial-mesenchymal transition (EMT) [12, 13]. Several studies have reported a correlation of YAP1 expression with aggressive clinical characteristics and low survival [19,20,21,22,23,24,25,26,27,28,29] This evidence suggests that YAP1 is a potential therapeutic target, and that its pharmacologic or genetic inactivation may suppress tumor progression and improve drug sensitivity. The possible clinical relevance of YAP1 subcellular localization is not clearly defined
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