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The Prolyl Isomerase Pin1 Acts Synergistically with CDK2 to Regulate the Basal Activity of Estrogen Receptor α in Breast Cancer

Lucchetti, C
; 
Caligiuri, I
; 
Toffoli, G
; 
Giordano, A
; 
Rizzolio, F
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Journal Article
Date
2013-02-04
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Binding Sites
 Breast Neoplasms
 Cell Line, Tumor
 Cyclin-Dependent Kinase 2
 Drug Resistance, Neoplasm
 Estrogen Receptor alpha
 Female
 Gene Expression Regulation, Neoplastic
 Humans
 Mutagenesis, Site-Directed
 NIMA-Interacting Peptidylprolyl Isomerase
 Peptidylprolyl Isomerase
 Phosphatidylinositol 3-Kinases
 Phosphorylation
 Protein Binding
 Serine
 Signal Transduction
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http://hdl.handle.net/20.500.12613/5414
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10.1371/journal.pone.0055355
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. © 2013 Lucchetti et al.
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