The ubiquitin ligase RNF181 stabilizes ER? and modulates breast cancer progression.

ABSTRACT: ER? positive breast cancer accounts for 70% of breast malignancies. Compared with ER? negative types, ER? positive breast cancer could be effective controlled by endocrine therapy. However, more than half of the patients will develop endocrine resistance, making it an important clinical issue for breast cancer therapy. Endocrine resistance might be caused by multiple alternations, including the components of ER? signaling, during tumor progression. Thus, it is urgent and necessary to uncover the molecular mechanisms that controls ER? expression and stability to improve breast cancer therapeutics. In our current study, we identifies that the ubiquitin ligase RNF181 stabilizes ER? and facilitates breast cancer progression. The expression of RNF181 is correlated with ER? level in human breast tumors and relates to poor survival in endocrine-treated patients. RNF181 depletion inhibits breast cancer progression in vivo and in vitro, reduces ER? protein level and its target gene expression, such as PS2 and GREB1. Unbiased RNA sequencing analysis indicates RNF181 is necessary for ER? signature gene expression in whole genomic level. Immuno-precipitation assays indicate that RNF181 associates with ER? and promotes its stability possibly via inducing ER? K63-linked poly-ubiquitination. In conclusion, our data implicate a non-genomic mechanism by RNF181 via stabilizing ER? protein controls ER? target gene expression linked to breast cancer progression.

SUBMITTER: Zhu J 

PROVIDER: S-EPMC7605433 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature