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Pin1 modulates ERα levels in breast cancer through inhibition of phosphorylation-dependent ubiquitination and degradation

Oncogene volume 33, pages 1438–1447 (2014)Cite this article

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Abstract

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

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Acknowledgements

We thank McArdle Laboratories for Cancer Research for support of this project. We also thank the UW Carbone Comprehensive Cancer Center (UWCCC) for use of its shared services to complete this research. We thank Drs Pierre Chambon, Vladimir Spiegelman, Robert Kalejta and Greg Finn for providing us appropriate expression plasmids and reagents. We also thank Dr Wei Xu for insightful comments. This work was supported by NIH grants CA159578 (to E.T.A.) and T32 CA009135 (to P.R.) and a sponsored research award from Genoptix/Novartis (to D.R.).

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  1. Department of Oncology, UW Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI, USA

    P Rajbhandari, N M Solodin, S J Ellison-Zelski & E T Alarid

  2. Department of Pathology, Yale University Medical School, New Haven, CT, USA

    K A Schalper & D L Rimm

  3. Department of Medicine, Cancer Biology Program, Beth Isreal Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    K Ping Lu

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Rajbhandari, P., Schalper, K., Solodin, N. et al. Pin1 modulates ERα levels in breast cancer through inhibition of phosphorylation-dependent ubiquitination and degradation. Oncogene 33, 1438–1447 (2014). https://doi.org/10.1038/onc.2013.78

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