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Abstract
Breast cancer is the most common malignancy for women worldwide, while Triple Negative Breast Cancer (TNBC) accounts for 20% in all patients. Compared with estrogen receptor positive breast cancer, which could be effectively controlled via endocrine therapy, TNBC is more aggressive and worse in prognosis. It is therefore urgent and necessary to develop a novel therapeutic strategy for TNBC treatment. Recent studies identified Hippo signaling is highly activated in TNBC, which could be a driving pathway for TNBC progression. In our study, we determine RNF187 as a negative regulator for Hippo signaling activation. RNF187 depletion significantly decreases cell migration and invasion capacity in TNBC. These effects could be rescued by further YAP depletion. Depletion of RNF187 increases the YAP protein level and Hippo signaling target genes, such as CTGF and CYR61 in TNBC. Immuno-precipitation assay shows that RNF187 associates with YAP, promoting its degradation possibly via inducing YAP K48-dependent poly-ubiquitination. Interestingly, Our clinical data reveals that RNF187 reversely correlates with YAP protein level and Hippo target genes. RNF187 tends to correlate with good prognosis in TNBC patients. Our study provides evidence to establish a proteolytic mechanism in regulation Hippo signaling activation in TNBC.
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1 Xinxiang Medical University, Henan Key Laboratory of Immunology and Targeted Therapy, School of Laboratory Medicine, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang, P.R. China (GRID:grid.412990.7) (ISNI:0000 0004 1808 322X); Xinxiang Medical University, School of Stomatology, Xinxiang, P.R. China (GRID:grid.412990.7) (ISNI:0000 0004 1808 322X)
2 Xinxiang Medical University, Henan Key Laboratory of Immunology and Targeted Therapy, School of Laboratory Medicine, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang, P.R. China (GRID:grid.412990.7) (ISNI:0000 0004 1808 322X); Xinxiang Medical University, School of International Education, Xinxiang, P.R. China (GRID:grid.412990.7) (ISNI:0000 0004 1808 322X)
3 Shandong University, Department of Pathology, Qilu Hospital, Jinan, P.R. China (GRID:grid.27255.37) (ISNI:0000 0004 1761 1174)
4 Shandong University, School of Basic Medical Science, Jinan, P.R. China (GRID:grid.27255.37) (ISNI:0000 0004 1761 1174)
5 Xinxiang Medical University, Henan Key Laboratory of Immunology and Targeted Therapy, School of Laboratory Medicine, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang, P.R. China (GRID:grid.412990.7) (ISNI:0000 0004 1808 322X)
6 Zhongnan Hospital of Wuhan University, Department of Thyroid and Breast Surgery, Wuhan, China (GRID:grid.413247.7)
7 Guangdong Academy of Medical Science, Department of Radiology, Guangdong Provincial People’s Hospital, Guangzhou, P.R. China (GRID:grid.410643.4)
8 Wuhan University, School of Medicine, Wuhan, China (GRID:grid.49470.3e) (ISNI:0000 0001 2331 6153)
9 Xinxiang University, School of Medicine, Xinxiang, P.R. China (GRID:grid.495434.b) (ISNI:0000 0004 1797 4346)