Pin1 modulates ER? levels in breast cancer through inhibition of phosphorylation-dependent ubiquitination and degradation.

ABSTRACT: Estrogen receptor-alpha (ER?) is an important biomarker used to classify and direct therapy decisions in breast cancer (BC). Both ER? protein and its transcript, ESR1, are used to predict response to tamoxifen therapy, yet certain tumors have discordant levels of ER? protein and ESR1, which is currently unexplained. Cellular ER? protein levels can be controlled post-translationally by the ubiquitin-proteasome pathway through a mechanism that depends on phosphorylation at residue S118. Phospho-S118 (pS118-ER?) is a substrate for the peptidyl prolyl isomerase, Pin1, which mediates cis-trans isomerization of the pS118-P119 bond to enhance ER? transcriptional function. Here, we demonstrate that Pin1 can increase ER? protein without affecting ESR1 transcript levels by inhibiting proteasome-dependent receptor degradation. Pin1 disrupts ER? ubiquitination by interfering with receptor interactions with the E3 ligase, E6AP, which also is shown to bind pS118-ER?. Quantitative in situ assessments of ER? protein, ESR1, and Pin1 in human tumors from a retrospective cohort show that Pin1 levels correlate with ER? protein but not to ESR1 levels. These data show that ER? protein is post-translationally regulated by Pin1 in a proportion of breast carcinomas. As Pin1 impacts both ER? protein levels and transactivation function, these data implicate Pin1 as a potential surrogate marker for predicting outcome of ER?-positive BC.

SUBMITTER: Rajbhandari P 

PROVIDER: S-EPMC3815749 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature