Abstract
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.
Highlights
Breast cancer (BC) is the second leading cause of death in women in the United States and is the most common cancer that affects women
Loss of function of kidney and brain expressed protein (KIBRA) induces epithelial-to-mesenchymal transition (EMT) and mammary epithelial cell transformation We previously demonstrated that KIBRA interacts with non-receptor tyrosine phosphatase (PTPN14) and synergistically activates LATS1 and inhibits Yes-associated protein 1 (YAP1) oncogenic function [8]
Consistent with a previous report [19], we observed that KIBRA knockdown caused a transition from an epithelial-like cell morphology to a mesenchymal-like cell morphology (Figure 1B); this finding indicated that the loss of KIBRA function induced EMT
Summary
Breast cancer (BC) is the second leading cause of death in women in the United States and is the most common cancer that affects women. Pathways and protein interactions that drive this disease are continually being identified and characterized; the key signaling nodes remain elusive [1]. The Hippo signaling pathway was first identified in Drosophila melanogaster and controls cell proliferation, apoptosis, and organ size [2, 3]. Deregulation of Hippo signaling can drive progression through the activation of its effector molecules YAP1 (Yes-associated protein 1) and TAZ (transcriptional co-activator with PDZ binding motif) [4]. The nuclear translocation of YAP1 and TAZ is associated with www.oncotarget.com increased breast cancer progression, metastasis, epithelialto-mesenchymal transition (EMT), epithelial stem cell regeneration, and therapeutic resistance [6]. In combination with non-receptor tyrosine phosphatase (PTPN14) and KIBRA, LATS1/2 phosphorylate the key effectors of Hippo signaling, YAP1 and TAZ [8, 9]. Phosphorylated YAP1/TAZ interact with the 14-33 proteins, sequestering YAP1/TAZ in the cytoplasm [10,11,12]. β-TrCP is recruited to phosphorylated YAP/ TAZ, which prompts their ubiquitination and subsequent proteasome degradation [13]
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