期刊
ONCOGENE
卷 33, 期 11, 页码 1438-1447出版社
SPRINGERNATURE
DOI: 10.1038/onc.2013.78
关键词
breast cancer; E3 ligase; proteasome; survival
资金
- NIH [CA159578, T32 CA009135]
- Genoptix/Novartis
Estrogen receptor-alpha (ER alpha) is an important biomarker used to classify and direct therapy decisions in breast cancer (BC). Both ER alpha protein and its transcript, ESR1, are used to predict response to tamoxifen therapy, yet certain tumors have discordant levels of ER alpha protein and ESR1, which is currently unexplained. Cellular ER alpha 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 alpha) is a substrate for the peptidyl prolyl isomerase, Pin1, which mediates cis-trans isomerization of the pS118-P119 bond to enhance ER alpha transcriptional function. Here, we demonstrate that Pin1 can increase ER alpha protein without affecting ESR1 transcript levels by inhibiting proteasome-dependent receptor degradation. Pin1 disrupts ER alpha ubiquitination by interfering with receptor interactions with the E3 ligase, E6AP, which also is shown to bind pS118-ER alpha. Quantitative in situ assessments of ER alpha protein, ESR1, and Pin1 in human tumors from a retrospective cohort show that Pin1 levels correlate with ER alpha protein but not to ESR1 levels. These data show that ER alpha protein is post-translationally regulated by Pin1 in a proportion of breast carcinomas. As Pin1 impacts both ER alpha protein levels and transactivation function, these data implicate Pin1 as a potential surrogate marker for predicting outcome of ER alpha-positive BC.
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