YAP1 inhibition radiosensitizes triple negative breast cancer cells by targeting the DNA damage response and cell survival pathways

Abstract

The Hippo pathway is an evolutionarily conserved signaling pathway that regulates proliferation and apoptosis to control organ size during developmental growth. Yes-associated protein 1 (YAP1), the terminal effector of the Hippo pathway, is a transcriptional co-activator and a potent growth promoter that has emerged as a critical oncogene. Overexpression of YAP1 has been implicated in promoting resistance to chemo-, radiation and targeted therapy in various cancers. However, the role of YAP1 in radioresistance in triple-negative breast cancer (TNBC) is currently unknown. We evaluated the role of YAP1 in radioresistance in TNBC in vitro, using two approaches to inhibit YAP1: 1) genetic inhibition by YAP1 specific shRNA or siRNA, and 2) pharmacological inhibition by using the small molecule inhibitor, verteporfin that prevents YAP1 transcriptional activity. Our findings demonstrate that both genetic and pharmacological inhibition of YAP1 sensitizes TNBC cells to radiation by inhibiting the EGFR/PI3K/AKT signaling axis and causing an increased accumulation of DNA damage. Our results reveal that YAP1 activation exerts a protective role for TNBC cells in radiotherapy and represents a pharmacological target to enhance the anti-tumor effects of DNA damaging modalities in the treatment of TNBC.

Phytochemicals inhibit migration of triple negative breast cancer cells by targeting kinase signaling

“…Activation of CHK2 has been associated with a decrease in invasive potential of cells in p53 mutant cancers [30]. Interestingly, fisetin and quercetin significantly increased pCHK2 levels in all nine TNBC cells by 6–170% and 13–187%, respectively.…”

Aberrant Promoter Methylation of YAP Gene and its Subsequent Downregulation in Indian Breast Cancer Patients

“…As reported in literature, the function of YAP on being a tumor suppressor or oncogene remains controversial. In many solid tumors YAP promotes tumor growth, followed by its progression and metastasis [ 37 ]. Hippo pathway is inactivated by any changes in the tissue microenvironment or stimulation of cell by intracellular or extracellular signals thereby hyperactivating YAP.…”

“…The hyperactivated YAP enters nucleus and interacts with DNA-binding transcription factors like TEA domain/Transcription Enhancer Factor (TEAD) family, p63/p73, ErbB, Smad, and RUNX1/2 [ 38 , 39 ]. TEAD, a key transcription factor in hippo pathway acting downstream from YAP is required for the gene expression, cell growth, epithelial to mesenchymal transition, anchorage-independent growth, and oncogenic transformation of YAP [ 11 , 37 , 39 ]. YAP binds to TEAD family of transcription factors and stimulates the downstream transcription of anti-apoptotic and proliferative genes; thereby promoting oncogenesis [ 39 ].…”

Personalizing Breast Cancer Irradiation Using Biology: From Bench to the Accelerator

“…For instance, Yes-associated protein 1 (YAP1), which is the terminal effector of the Hippo pathway is involved in TNBC radioresistance. The use of verteporfin, a YAP1 inhibitor, radiosensitized TNBC cell lines by inhibiting EGFR/PI3K/AKT signaling pathway and by increasing DNA damages ( 18 ). Other preclinical approaches have been developed as the use of niclosamide, a potent inhibitor of Wnt/β-catenin signaling ( 19 ).…”