Abstract
Abstract A hypoxia-related protein, REDD1 (regulated in development and DNA damage response 1), inhibits the mammalian target of rapamycin (mTOR) signaling pathway in normal cells under hypoxic condition, but a loss of REDD1 causes tumorigenesis in certain tumor cells. The purpose of this study is to investigate REDD 1 -mediated regulation of the mTOR pathway in breast cancer. Tissue microarray included samples from 224 patients with breast cancer, and 30 patients with papilloma were used as control group. The immunohistochemistry (IHC) such as estrogen receptor (ER), progesterone receptor (PR), HER-2, epithelial growth factor receptor (EGFR), cytokeratin (CK) 5/6, Glut-1, HIF-1α, REDD 1, AMPK ≥1, 14-3-3 σ, PTEN, phospho-Akt, phospho-mTOR, phospho-S6, and Ki-67 were performed. Phenotypic classification of breast cancer was performed based on the results of IHC for ER, PR, and HER-2 and fluorescent in Situ Hybridization (FISH) for HER-2: luminal A, luminal B, HER-2 overexpression, and triple negative breast cancer (TNBC). Glut-1and HIF-1 alpha were more highly expressed in TNBC, HER-2 overexpressiontype, and papilloma than luminal A and B (P = 0.000). REDD1 expression was higher in papilloma than breast cancer (P = 0.000), but no difference was found among the 4 breast cancer phenotypes (P = 0.307). HIF-1α expression was an important factor of decreased time to disease free survival and overall survival in univariate analysis (P = 0.003, and 0.000, respectively) and multivariate Cox analysis (P = 0.018, odd ratio: 7.6, and P = 0.002, odd ratio: 13.7, respectively). Among human breast cancer phenotypes, HER-2 overexpression and TNBC type demonstrated down-regulation of REDD1 under hypoxic tumor environment. In HER-2 overexpression and TNBC type, tumor cell proliferation and survival in hypoxic tumor environment could be possible due to dysinhibition of the mTOR pathway and HIF-1α stabilization through down-regulation of REDD1. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-08-13.
Published Version
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