The GPER1/SPOP axis mediates ubiquitination-dependent degradation of ER? to inhibit the growth of breast cancer induced by oestrogen.

G protein-coupled oestrogen receptor 1 (GPER1), predicted to be a novel oestrogen receptor, has been linked to the development and progression of breast cancer. However, the molecular mechanisms underlying its functions remain elusive. Here, we show that the protein levels of GPER1 are negatively associated with those of ER? and ...
that higher expression of GPER1 correlated with a better clinical outcome in oestrogen receptor-positive (ER+) breast cancer patients. Activation of GPER1 decreases ER? protein levels, which subsequently suppresses ER?-mediated transcription and target gene expression but does not affect its mRNA expression in ER + breast cancer cells. A mechanistic study revealed that GPER1 mediates ubiquitin (Ub)-proteasome-dependent degradation of ER? via upregulation of the Cullin3-based E3 ubiquitin ligase adaptor protein speckle-type POZ protein (SPOP), and depletion of SPOP abrogates GPER1-induced ER? ubiquitination and degradation. Functionally, GPER1 activation inhibits 17?-oestradiol (E2)-induced ER + breast cancer cell proliferation, migration, and invasion in vitro and tumour growth in vivo. Our findings reveal a novel mechanism by which GPER1 negatively modulates the ER? signalling pathway via promoting its ubiquitin-proteasome-dependent degradation, which may contribute to its inhibition of breast cancer progression.
Mesh Terms:
Animals, Breast Neoplasms, Cell Line, Tumor, Cell Movement, Cell Proliferation, Estradiol, Estrogen Receptor alpha, Estrogens, Female, Humans, MCF-7 Cells, Mice, Mice, Nude, Middle Aged, Nuclear Proteins, Proteasome Endopeptidase Complex, Receptors, Estrogen, Receptors, G-Protein-Coupled, Repressor Proteins, Signal Transduction, Ubiquitin, Ubiquitin-Protein Ligases, Ubiquitination, Up-Regulation
Cancer Lett
Date: Dec. 01, 2020
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