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.
Highlights
Triple negative breast cancer[1] (TNBC) is the most aggressive[2,3] subtype of breast cancer, which harbors high genetic heterogeneity[4]
In order to investigate the role of RNF187 in triple negative breast cancer cells, we utilized BT549 and MDAMB231 cells to carry out most of the experiments
RNF187 inhibits Hippo signaling in triple negative breast cancer cells
Summary
Triple negative breast cancer[1] (TNBC) is the most aggressive[2,3] subtype of breast cancer, which harbors high genetic heterogeneity[4]. Compared with hormone receptor positive breast cancer, TNBC has a high rate of genomic mutation, gene amplification, and deletion[5]. It harbors different kinds of tumor suppressive gene mutations including P53 and Rb. It harbors different kinds of tumor suppressive gene mutations including P53 and Rb It is still lack of effective “targeted”. Hippo pathway controls the tissue growth and organ size by simultaneously restricting cell growth and cell proliferation while promoting cell death. The core Hippo pathway consists of a kinase cascade: the upstream kinase MST1/2 activates a downstream kinase LATS1/2, leading to phosphorylation and inactivation of a transcriptional cofactors YAP/TAZ8. YAP protein is the most important downstream activator for Hippo signaling, which shuttle between the
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