Prolyl isomerase PIN1 negatively regulates SGK1 stability to mediate tamoxifen resistance in breast cancer cells.

Endocrine therapies that inhibit oestrogen receptor (ER)-α signaling are the most common and effective treatment for ER-α-positive breast cancer. The present study aimed to elucidate the mechanisms by which down-regulation of serum- and glucocorticoid-inducible protein kinase-1 (SGK1) expression confers tamoxifen resistance in breast cancer.SGK1 expression and the cytotoxic effects of ...
combinatorial 4-hydroxy-tamoxifen (4-OHT) treatment with SGK1 overexpression were investigated by immunoblotting, bromodeoxyuridine incorporation, and soft agar assay.We showed that PIN1 down-regulates SGK1 expression through interaction with and ubiquitination of SGK1. PIN1 silencing in MCF7 cells increased SGK1 expression. In tamoxifen-resistant human breast cancer, immunohistochemical staining analysis showed an inverse correlation between SGK1 expression and severity of tamoxifen resistance. Importantly, 4-OHT in combination with overexpression of SGK1 increased cleavage of poly-(ADP-ribose) polymerase and DNA fragmentation to inhibit clonogenic growth of tamoxifen-resistant MCF7 (TAMR-MCF7) cells.We suggest that PIN1-mediated SGK1 ubiquitination is a major regulator of tamoxifen-resistant breast cancer cell growth and survival.
Mesh Terms:
Base Sequence, Cell Line, Tumor, DNA Primers, Drug Resistance, Neoplasm, Enzyme Stability, Female, Humans, Immediate-Early Proteins, Peptidylprolyl Isomerase, Protein-Serine-Threonine Kinases, Real-Time Polymerase Chain Reaction, Tamoxifen
Anticancer Res.
Date: Feb. 01, 2015
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