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.
Highlights
Breast cancer is the most common cancer among women and the leading cause of cancer-related death worldwide
When the analysis was restricted to TNBC patients, YAP1 mRNA expression correlated with decreased RelapseFree Survival (RFS), supporting its role as an oncogene in TNBC
YAP1 expression is elevated in a number of human malignancies and its expression has been suggested as a negative prognostic factor for cancer [10,11,12,13,14]
Summary
Breast cancer is the most common cancer among women and the leading cause of cancer-related death worldwide. Despite advances in molecular classification and targeted molecular therapy, breast cancer incidence and mortality rate remain high [1,2,3,4,5]. TNBC is a subset of the basal-like breast cancer group, characterized by the lack of estrogen receptor (ER), progesterone receptor (PR) and Her-2/EGFR2 [2, 3]. TNBC is an invasive and aggressive breast cancer subtype that accounts for 10–15% of all breast cancers and is associated with poor prognosis, a high rate of recurrence, and distant metastasis. Because of the lack of approved targeted therapy, chemotherapy remains the mainstay of treatment for early and advanced disease. Better therapeutic tools and new treatment options for TNBC are urgently needed
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