Loss of KIBRA function activates EGFR signaling by inducing AREG

The cover for issue 52 of Oncotarget features Figure 5, "Low KIBRA expression predicts poor breast cancer patient outcome," by Mussell, et al.

The clinical significance of KIBRA deregulation and the underlying mechanisms by which KIBRA regulates breast cancer initiation and progression remain poorly understood. Mechanistically, the researchers observed that inhibiting KIBRA induced growth factor-independent cell proliferation in 2D and 3D culture due to the secretion of amphiregulin, an epidermal growth factor receptor ligand.

Dr. Jianmin Zhang from the Department of Cancer Genetics & Genomics, Roswell Park Cancer Institute, Buffalo, NY, USA said "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."

Figure 5: Low KIBRA expression predicts poor breast cancer patient outcome. Kaplan-Meier overall survival (OS) and relapse-free survival (RFS)analysis of breast cancer patients using a median split of KIBRA gene expression (KM-plotter). The Log-Rank test was used to measure the statistical difference between the high and low KIBRA groups for Kaplan-Meier curves.

The Hippo signaling pathway was first identified in Drosophila melanogaster and controls cell proliferation, apoptosis, and organ size. In breast cancer, deregulation of Hippo signaling can drive progression through the activation of its effector molecules YAP1 and TAZ. In combination with non-receptor tyrosine phosphatase and KIBRA, LATS1/2 phosphorylate the key effectors of Hippo signaling, YAP1 and TAZ. KIBRA has been shown to exert its tumor suppressive effects through interaction with Merlin and Expanded, two upstream regulators of Hippo signaling.

Notwithstanding these findings, little is known about the detailed molecular mechanisms linking KIBRA to the regulation of the Hippo pathway and tumorigenesis. Dr. Jianmin Zhang concluded, "This approach might enable early intervention in breast cancer patients and provide novel therapeutic avenues for breast cancer treatment."

Full text - https://doi.org/10.18632/oncotarget.25724

Correspondence to - Jianmin Zhang - [email protected]

Keywords - Hippo pathway, EGFR signaling, 3D culture, breast tumorigenesis