<p>Inhibition of Yes-Associated Protein-1 (YAP1) Enhances the Response of Invasive Breast Cancer Cells to the Standard Therapy</p>

Abstract

Purpose The deregulation of the Hippo pathway results in translocation ofYes-associated protein-1 (YAP1) to the nucleus to exert an oncogenic effect. This effect has been demonstrated in several malignancies, yet, in breast cancer (BC), it remains controversial. The present study aimed to investigate the significance of YAP1 expression in BC, its relation to cancer stem cells (CSCs), and the effect of its inhibition on tumor cell survival. Patients and Methods We evaluated the expression of YAP1 protein and gene using immunohistochemistry (IHC) and RT-qPCR in FFPE tissue from normal and breast cancer cases. We also studied its association with CSC expression ( OCT4, NANOG , and SOX2 ) and with different clinicopathologic characteristics. Two BC cell lines (MCF7 and MDA-MB-231) were exposed to different concentrations of YAP1 inhibitor “verteporfin” and cell viability was subsequently assessed. Results YAP1 mRNA was higher in BC compared to the normal breast tissue (p-value=0.040) and was higher in luminal tumors compared to triple-negative breast cancer (TNBC) (p-value= 0.017). Its expression in tumors was significantly associated with the expression of pluripotency markers ( OCT4 and NANOG ) (p-value= 0.030 and 0.035, respectively) and its inhibition resulted in a significant reduction of CSC expression in both MCF-7 and MDA-MB-231 cells. YAP1 nuclear expression by IHC, which signifies its activation, was more evident in invasive carcinomas compared to normal breast tissue and in-situ foci where the expression was limited to the cytoplasm. The pretreatment of BC cells (MCF7 and MDA-MB-231) with YAP1 inhibitor “verteporfin” resulted in their sensitization to the effect of tamoxifen and doxorubicin, respectively, and significantly decreased tumor cell proliferation and survival. Conclusion Our results imply that YAP1 is highly expressed and activated in BC and its inhibition could represent a possible novel therapeutic strategy that should be further explored and investigated to improve the outcome of breast cancer patients.

Tripartite motif-containing protein 6 facilitates growth and migration of breast cancer through degradation of STUB1

“…23 YAP1 functioned as an oncogene to promote breast cancer survival, 24 and repression of YAP1 contributed to suppression of breast cancer progression. 25,26 YAP1 was reported to be the target of STUB1 in gastric cancer cells, 27 and our results showed that forced STUB1 attenuated TRIM6-induced increase in YAP1. In addition, knockdown of TRIM6 repressed in vivo breast cancer growth through increasing of STUB1 and decreasing of YAP1.…”

Effects of YAP1 and SFRP2 overexpression on the biological behavior of colorectal cancer cells and their molecular mechanisms

“…CRC is caused by multiple factors and multiple mechanisms, which are associated with abnormal cell signaling pathways, such as the Hippo/Yes-associated protein 1 (YAP1) pathway and the Wnt/β-catenin pathway (3,4). In the Hippo/YAP1 signaling pathway, the activation of YAP1 is associated with tumor acquisition of malignant characteristics, including anti-cancer therapy resistance, the metastasis of cancer stem cells, and epithelial-mesenchymal transformation (5)(6)(7). In addition, YAP1 has been shown to be associated with poor prognosis and reduced survival in many human cancers (8)(9)(10).…”

Expression characteristics of the yes-associated protein in breast cancer: A meta-analysis

“…[37] The mRNA level of YAP and its receptors is also elevated in breast cancer compared with that in normal breast tissues. [38] Some functional regions of YAP bind to Kruppel-like factor 5 (KLF5), a transcription factor that promotes breast cell proliferation and survival, thereby regulating cell proliferation. [12] The current meta-analysis of this study, however, indicated contradictory results between non-TNBC and TNBC by summarizing 10 case-control studies.…”