Loss of KIBRA function activates EGFR signaling by inducing AREG
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Ashley L. Mussell1,*, Kayla E. Denson1,4,*, He Shen1, Yanmin Chen1, Nuo Yang2, Costa Frangou3 and Jianmin Zhang1
1Department of Cancer Genetics & Genomics, Roswell Park Cancer Institute, Buffalo, NY, USA
2Department of Anesthesiology, Jacobs School of Medicine & Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA
3Harvard T.H. Chan School of Public Health, Molecular and Integrative Physiological Sciences, Boston, MA, USA
4Current address: Frontier Science Foundation, Amherst, NY, USA
*These authors have contributed equally to this work
Jianmin Zhang, email: Jianmin.firstname.lastname@example.org
Keywords: Hippo pathway; EGFR signaling; 3D culture; breast tumorigenesis
Received: April 30, 2018 Accepted: June 19, 2018 Published: July 06, 2018
The Hippo signaling pathway is a central regulator of organ size, tissue homeostasis, and tumorigenesis. KIBRA is a member of the WW domain-containing protein family and has recently been reported to be an upstream protein in the Hippo signaling pathway. However, the clinical significance of KIBRA deregulation and the underlying mechanisms by which KIBRA regulates breast cancer (BC) initiation and progression remain poorly understood. Here, we report that KIBRA knockdown in mammary epithelial cells induced epithelial-to-mesenchymal transition (EMT) and increased cell migration and tumorigenic potential. Mechanistically, we observed that inhibiting KIBRA induced growth factor-independent cell proliferation in 2D and 3D culture due to the secretion of amphiregulin (AREG), an epidermal growth factor receptor (EGFR) ligand. Also, we show that AREG activation in KIBRA-knockdown cells depended on the transcriptional coactivator YAP1. Significantly, decreased expression of KIBRA is correlated with recurrence and reduced BC patient survival. In summary, this study elucidates the molecular events that underpin the role of KIBRA in BC. As a result, our work provides biological insight into the role of KIBRA as a critical regulator of YAP1-mediated oncogenic growth, and may have clinical potential for facilitating patient stratification and identifying novel therapeutic approaches for BC patients.
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