Breast Cancer: Targets and Therapy (Nov 2020)
Inhibition of Yes-Associated Protein-1 (YAP1) Enhances the Response of Invasive Breast Cancer Cells to the Standard Therapy
Abstract
Maha Guimei,1,2 Sana Alrouh,3 Maha Saber-Ayad,2– 4 Shirin A Hafezi,3 Arya Vinod,3 Surendra Rawat,3 Yazan Wardeh,5 Tala Mohamad Bakkour,5 Ahmed Taher El-Serafi3,6,7 1Department of Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt; 2Clinical Sciences Department, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; 3Sharjah Institute of Medical Research, University of Sharjah, Sharjah, United Arab Emirates; 4Department of Pharmacology, College of Medicine, Cairo University, Cairo, Egypt; 5College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; 6Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt; 7Department of Biomedical and Clinical Sciences, Linköping University, Linköping, SwedenCorrespondence: Maha GuimeiDepartment of Pathology, Faculty of Medicine, Alexandria University, 17 Champollion Street, Alexandria, EgyptTel +20 1005384268Email [email protected]: 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.Keywords: breast cancer, YAP1, Hippo pathway, cancer stem cells, verteporfin
