Proyl isomerase Pin1 facilitates ubiquitin-mediated degradation of cyclin-dependent kinase 10 to induce tamoxifen resistance in breast cancer cells

• Published in: Oncogene Vol. 31; no. 34; pp. 3845 - 3856
• Main Authors: Khanal, P, Yun, H J, Lim, S C, Ahn, S G, Yoon, H E, Kang, K W, Hong, R, Choi, H S
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 23.08.2012
• Subjects: Animals; Antineoplastic Agents, Hormonal - pharmacology; Apoptosis - drug effects; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Care and treatment; Cell Line, Tumor; Cell Proliferation - drug effects; Cell survival; Cell Survival - drug effects; Cells, Cultured; Cyclin-dependent kinase; Cyclin-dependent kinase 10; Cyclin-dependent kinases; Cyclin-Dependent Kinases - genetics; Cyclin-Dependent Kinases - metabolism; Development and progression; DNA fragmentation; Dosage and administration; Drug Resistance, Neoplasm - genetics; Embryo fibroblasts; Embryo, Mammalian - cytology; Endocrine therapy; Estrogen; Estrogen receptors; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Gene expression; Health aspects; HEK293 Cells; Humans; Immunoblotting; Kinases; Mice; Mice, Knockout; NIMA-Interacting Peptidylprolyl Isomerase; Patient outcomes; Peptidylprolyl isomerase; Peptidylprolyl Isomerase - genetics; Peptidylprolyl Isomerase - metabolism; Phosphorylation; Phosphorylation - drug effects; Physiological aspects; Pin1 protein; Poly(ADP-ribose) polymerase; Protein Binding; Proteolysis; Proto-Oncogene Proteins c-raf - metabolism; Raf protein; RNA Interference; Signal transduction; Tamoxifen; Tamoxifen - pharmacology; Ubiquitin; Ubiquitin - metabolism; Ubiquitination; South Korea
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2011.548

Endocrine therapies that inhibit estrogen receptor (ER)-α signaling are the most common and effective treatment for ER-α-positive breast cancer. However, the use of these agents is limited by the frequent development of resistance. The aim of this study was to elucidate the mechanisms by which downregulation of CDK10 expression confers resistance to tamoxifen in breast cancer. Here, we show that peptidyl-prolyl isomerase Pin1 downregulates CDK10 protein as a result of its interaction with and ubiquitination of CDK10, thereby affecting CDK10-dependent Raf-1 phosphorylation (S338). Pin1(-/-) mouse embryonic fibroblasts (MEFs) show higher CDK10 expression than Pin1(+/+) MEFs, whereas CDK10 protein was downregulated in the rescued Pin1(-/-) MEFs after reexpression of Pin1. Pin1 silencing in SKBR-3 and MCF7 cells increased the CDK10 expression. In human tamoxifen-resistant breast cancer and tamoxifen-resistant MCF7 cells, immunohistochemical staining and immunoblotting analysis shows an inverse correlation between the expression of CDK10 and the degree of tamoxifen resistance. There was also a positive correlation between the high level of P-Raf-1 (Ser338) and Pin1 in human tamoxifen-resistant breast cancer and tamoxifen-resistant MCF7 (TAMR-MCF7) cells. Importantly, 4-OH tamoxifen (4-OHT), when used in combination with overexpressed CDK10 or Raf-1 inhibitor, increased cleaved PARP and DNA fragmentation to inhibit cologenic growth of MCF7 cells and Tamoxifen-resistant MCF7 cells, respectively. On the basis of these findings, we suggest that the Pin1-mediated CDK10 ubiquitination is a major regulator of tamoxifen-resistant breast cancer cell growth and survival.