The ubiquitin ligase RNF181 stabilizes ERα and modulates breast cancer progression

ER alpha positive breast cancer accounts for 70% of breast malignancies. Compared with ER alpha negative types, ER alpha 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 alpha signaling, during tumor progression. Thus, it is urgent and necessary to uncover the molecular mechanisms that controls ER alpha expression and stability to improve breast cancer therapeutics. In our current study, we identifies that the ubiquitin ligase RNF181 stabilizes ER alpha and facilitates breast cancer progression. The expression of RNF181 is correlated with ER alpha 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 alpha protein level and its target gene expression, such as PS2 and GREB1. Unbiased RNA sequencing analysis indicates RNF181 is necessary for ER alpha signature gene expression in whole genomic level. Immuno-precipitation assays indicate that RNF181 associates with ER alpha and promotes its stability possibly via inducing ER alpha K63-linked poly-ubiquitination. In conclusion, our data implicate a non-genomic mechanism by RNF181 via stabilizing ER alpha protein controls ER alpha target gene expression linked to breast cancer progression.