TY - JOUR T1 - Prolyl Isomerase PIN1 Negatively Regulates SGK1 Stability to Mediate Tamoxifen Resistance in Breast Cancer Cells JF - Anticancer Research JO - Anticancer Res SP - 785 LP - 794 VL - 35 IS - 2 AU - ARA JO AU - HYO JEONG YUN AU - JIN YOUNG KIM AU - SUNG-CHUL LIM AU - HUI JEONG CHOI AU - BONG SEOK KANG AU - BU-YOUNG CHOI AU - HONG SEOK CHOI Y1 - 2015/02/01 UR - http://ar.iiarjournals.org/content/35/2/785.abstract N2 - Background/Aim: 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. Materials and Methods: 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. Results: 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. Conclusion: We suggest that PIN1-mediated SGK1 ubiquitination is a major regulator of tamoxifen-resistant breast cancer cell growth and survival. ER -