PI3K Positively Regulates YAP and TAZ in Mammary Tumorigenesis Through Multiple Signaling Pathways

Abstract

Breast cancer is a leading cause of death in women worldwide. Active mutations of PI3K catalytic subunit PIK3CA (e.g., H1047R) and amplification of its homolog PIK3CB are observed in a large number of breast cancers. In recent years, aberrant activation of Transcriptional coactivator with PDZ binding motif (TAZ) and its paralog Yes-associated protein (YAP) have also been found to be important for breast cancer development and progression. However, whether PI3K interacts with YAP/TAZ during mammary tumorigenesis is unknown. Through a systematic gain-of-function screen for kinases involved in mammary tumorigenesis, we identified PIK3CB as a transformation-inducing kinase in breast cells. We further determined that PIK3CB positively regulates YAP and TAZ to promote transformation and inhibit mammary cell death PIK3CB coexpression with TAZ, rather than PIK3CB or TAZ alone, in human MCF10A nontumorigenic mammary cells is sufficient for tumor formation in mice Interestingly, we also determined that PIK3CA-H1047R enhances YAP and TAZ activity in mammary tumorigenesis Mechanistically, the regulation of YAP/TAZ by both PIK3CA and PIK3CB occurs through multiple signaling pathways including LATS-dependent and LATS-independent pathways. Therefore, in this study, we determine that PI3K and YAP/TAZ interact to promote breast cancer cell transformation. This study provides the first evidence that the Hippo pathway effectors TAZ and YAP are critical mediators of PI3K-induced mammary tumorigenesis and synergistically function together with PI3K in transformation of mammary cells. These findings may provide a novel rationale for targeting YAP/TAZ alone or in combination with PI3K inhibitors for breast cancer therapy in the future. .

Novel prognostic and predictive microRNA targets for triple‐negative breast cancer

“…Our in silico analysis revealed that many of our miRNAs associated with OS and RFS target components of the hippo signaling pathway. More specifically, we found that miR-30a targets the effector protein YAP, an oncogene commonly dysregulated in cancer and linked to poor prognosis in breast cancer (78)(79)(80)(81). With the use of qRT-PCR, we reveal an inverse relationship between miR-30a and YAP in human normal (MCF-10A) and TNBC (MDA-MB-231) cells and show that overexpression of miR-30a in MDA-MB-231 cells significantly downregulates YAP to levels characteristic of MCF-10A cells.…”

Genome-wide CRISPR screens of oral squamous cell carcinoma reveal fitness genes in the Hippo pathway

“…Intriguingly, we also observed enrichment of PIK3CA mutant (p=0.0003) among OSCC lines that are compensable for YAP1 or WWTR1. As recent studies have provided evidence that YAP1 and WWTR1 could mediate mutant PIK3CA-induced tumorigenesis ( Zhao et al, 2018 ) andother studies also suggested crosstalk between these Hippo pathway effectors with the PI3K-Akt pathway ( García-Escudero et al, 2018 ), confirmatory and mechanistic studies will be needed to delineate why YAP1 and WWTR1 function can be compensated in these PIK3CA -mutated cell lines, while distinct dependencies on either paralog are observed in PIK3CA wild-type lines. The functional loss of mutated FAT1 has also been reported to be associated with YAP1 activation in head and neck cancer ( Martin et al, 2018 ), however, no enrichment of FAT1 mutation was seen among the YAP1-dependent nor WWTR1-dependent models in this study.…”

YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy

“…[ 169 ] Recent evidence suggests that PI3K‐Akt signaling also inhibits the Hippo pathway to promote YAP/TAZ activation to drive cell proliferation and malignancy. [ 99,115,170‐178 ] Importantly, further work is necessary to identify the molecular mechanism by which PI3K‐Akt signaling inhibits the Hippo pathway. In addition, while PI3K‐Akt signaling appears necessary to promote YAP/TAZ activation, it is apparently not sufficient, as cells also require mechanical stimulation or other additional inputs to activate YAP/TAZ.…”

“…Specific inhibitors of PI3K and AKT are in clinical trials for cancer therapy. [ 169 ] Treatment of cancer cells with these inhibitors decreases YAP/TAZ nuclear translocation and activity, [ 170,172,173,176 ] suggesting a possible mechanism by which these inhibitors may reduce cancer growth and progression. Complete inhibition of YAP/TAZ in tumors may require dual inhibition of both PI3K‐AKT and SRC signaling.…”