The prolyl isomerase Pin1 acts synergistically with CDK2 to regulate the basal activity of estrogen receptor α in breast cancer

Chiara Lucchetti; Isabella Caligiuri; Giuseppe Toffoli; Antonio Giordano; Flavio Rizzolio

doi:10.1371/journal.pone.0055355

The prolyl isomerase Pin1 acts synergistically with CDK2 to regulate the basal activity of estrogen receptor α in breast cancer

PLoS One. 2013;8(2):e55355. doi: 10.1371/journal.pone.0055355. Epub 2013 Feb 4.

Authors

Chiara Lucchetti¹, Isabella Caligiuri, Giuseppe Toffoli, Antonio Giordano, Flavio Rizzolio

Affiliation

¹ Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, USA.

Abstract

In hormone receptor-positive breast cancers, most tumors in the early stages of development depend on the activity of the estrogen receptor and its ligand, estradiol. Anti-estrogens, such as tamoxifen, have been used as the first line of therapy for over three decades due to the fact that they elicit cell cycle arrest. Unfortunately, after an initial period, most cells become resistant to hormonal therapy. Peptidylprolyl isomerase 1 (Pin1), a protein overexpressed in many tumor types including breast, has been demonstrated to modulate ERalpha activity and is involved in resistance to hormonal therapy. Here we show a new mechanism through which CDK2 drives an ERalpha-Pin1 interaction under hormone- and growth factor-free conditions. The PI3K/AKT pathway is necessary to activate CDK2, which phosphorylates ERalphaSer294, and mediates the binding between Pin1 and ERalpha. Site-directed mutagenesis demonstrated that ERalphaSer294 is essential for Pin1-ERalpha interaction and modulates ERalpha phosphorylation on Ser118 and Ser167, dimerization and activity. These results open up new drug treatment opportunities for breast cancer patients who are resistant to anti-estrogen therapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Breast Neoplasms / genetics*
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Cell Line, Tumor
Cyclin-Dependent Kinase 2 / genetics*
Cyclin-Dependent Kinase 2 / metabolism
Drug Resistance, Neoplasm / genetics
Estrogen Receptor alpha / genetics*
Estrogen Receptor alpha / metabolism
Female
Gene Expression Regulation, Neoplastic*
Humans
Mutagenesis, Site-Directed
NIMA-Interacting Peptidylprolyl Isomerase
Peptidylprolyl Isomerase / genetics*
Peptidylprolyl Isomerase / metabolism
Phosphatidylinositol 3-Kinases / genetics*
Phosphatidylinositol 3-Kinases / metabolism
Phosphorylation
Protein Binding
Serine / metabolism
Signal Transduction

Substances

ESR1 protein, human
Estrogen Receptor alpha
NIMA-Interacting Peptidylprolyl Isomerase
Serine
CDK2 protein, human
Cyclin-Dependent Kinase 2
PIN1 protein, human
Peptidylprolyl Isomerase

Grants and funding

This work was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC) (A.G.), Special Program Molecular Clinical Oncology, 5×1000, (number 12214) (G.T.), European Research Council, Programme “Ideas”, proposal number 269051 (F.R., G.T.), Italian Ministry of Education MIUR (FIRB prot. RBAP11ETKA (G.T.)), Sbarro Health Research Organization (A.G.), Istituto Tumori Toscano ITT (A.G.), Human Health Foundation (A.G.) and Commonwealth of Pennsylvania (A.G.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.