title: Prolyl isomerase PIN1 negatively regulates SGK1 stability to mediate tamoxifen resistance in breast cancer cells.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  We suggest that PIN1-mediated SGK1 ubiquitination is a major regulator of tamoxifen-resistant breast cancer cell growth and survival.
authors: College of Pharmacy, School of Medicine, Chosun University, Gwangju, Republic of Korea.
authors: Ara
authors: A
authors: Jo
authors: College of Pharmacy, School of Medicine, Chosun University, Gwangju, Republic of Korea.
authors: Hyo Jeong
authors: HJ
authors: Yun
authors: College of Pharmacy, School of Medicine, Chosun University, Gwangju, Republic of Korea.
authors: Jin Young
authors: JY
authors: Kim
authors: Department of Pathology, School of Medicine, Chosun University, Gwangju, Republic of Korea.
authors: Sung-Chul
authors: SC
authors: Lim
authors: College of Pharmacy, School of Medicine, Chosun University, Gwangju, Republic of Korea.
authors: Hui Jeong
authors: HJ
authors: Choi
authors: Bio-Medical Research Institute, Kyungpook National University Hospital, Daegu, Republic of Korea.
authors: Bong Seok
authors: BS
authors: Kang
authors: Department of Pharmaceutical Science and Engineering, School of Convergence Bioscience and Technology, Seowon University, Cheongju, Republic of Korea.
authors: Bu-Young
authors: BY
authors: Choi
authors: College of Pharmacy, School of Medicine, Chosun University, Gwangju, Republic of Korea chs@chosun.ac.kr.
authors: Hong Seok
authors: HS
authors: Choi
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D019008:Drug Resistance, Neoplasm; D004795:Enzyme Stability; D005260:Female; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D013629:Tamoxifen / Q000494:pharmacology*; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D017931:DNA Primers; D017874:Immediate-Early Proteins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase; D017346:Protein Serine-Threonine Kinases; D013629:Tamoxifen; D000099184:Serum-Glucocorticoid Regulated Kinases; C000606846:PIN1 protein, human
keywords: PIN1; RAF1; SGK1; breast cancer; tamoxifen resistance; ubiquitination