Molecular profiling and computational network analysis of TAZ-mediated mammary tumorigenesis identifies actionable therapeutic targets.

Costa Frangou,Kayla E Wilson,Jianmin Zhang,Maxime Blijlevens,Nuo Yang,Jin Guo,He Shen,Norma J Nowak,Ying-Wei Li

doi:10.18632/oncotarget.2570

Abstract

Triple-negative breast cancer (TNBC) accounts for approximately 15-20% of all breast cancer (BC) cases and contributes disproportionately to BC mortality. TAZ, a key transducer of the Hippo pathway, has recently been demonstrated to confer breast cancer stem cell (CSC) traits. However, TAZ target genes and the underlying transcriptional regulatory pathways responsible for the CSC phenomenon remain unknown. Here, we demonstrate that the oncogenic activity of TAZ is essential for propagation of the malignant phenotype. We further show that constitutively active TAZ tumor-derived cells exhibit unique tumor-initiating properties, including increased self-renewal and metastatic seeding potential, acquired chemotherapy resistance and the ability to efficiently regenerate tumor formation in vivo. Combined digital RNA expression analysis and computational network approaches identify several signaling pathways that distinguish breast cancer tumor-initiating cells (T-ICs) from bulk tumor cells. We demonstrate the utility of this approach by repositioning the small molecule tyrosine kinase inhibitor, Dasatinib, which selectively targets T-ICs and inhibits TNBC growth in vivo.

Highlights

The Hippo pathway is an evolutionary conserved regulator of tissue growth and cell fate during mammalian development and regeneration, while deregulation of the Hippo pathway caused by gene mutation or anomalous protein expression has been linked to human diseases including cancer [1, 2]
We found that Dasatinib inhibited the anchorageindependent growth of TAZ-M#1 cells in soft-agar assay and reduced self-renewal as measured by mammosphere formation (Fig. 4B, C)
We examined the halfmaximal inhibitory concentration (IC50) values for Dasatinib and found that Triple-negative breast cancer (TNBC) cell lines were more sensitive to Dasatinib than luminal cell lines (Fig. 4E)

Summary

Introduction

The Hippo pathway is an evolutionary conserved regulator of tissue growth and cell fate during mammalian development and regeneration, while deregulation of the Hippo pathway caused by gene mutation or anomalous protein expression has been linked to human diseases including cancer [1, 2]. Over 20 regulators have been identified that intersect with core Hippo pathway components and potentially contribute to carcinogenesis. Central to the Hippo pathway are two key downstream effector proteins, YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) that are tightly regulated by a number of upstream signaling molecules, such as Mst1/2, Lats1/2 and RASSF family proteins [4, 5]. Inactivation of YAP/TAZ by the Hippo pathway is mediated primarily via cytoplasmic sequestration from 14-3-3 binding and protein degradation, respectively [6,7,8,9]. Hippo pathway-independent restriction of YAP/TAZ mediated by angiomotin, scribble, PTPN14, α-catenin and other junction protein sequestration mechanisms has been reported [10,11,12,13,14,15]

Methods

Results

Conclusion