Hemin inhibits cyclin D1 and IGF-1 expression via STAT5b under hypoxia in ERα-negative MDA-MB 231 breast cancer cells

2010 International Journal of Oncology  
Cyclin D1 and insulin-like growth factor 1 receptor are key regulators of cell proliferation that are overexpressed in most breast cancers. The purpose of the present study was to investigate the molecular mechanism by which hemin exerts its inhibitory effects on aggressive breast cancer cells. We found that hemin regulates cyclin D1 and IGF-1R proteins and insulin-like growth factor-1 gene expression through STAT5b in breast cancer cells. We confirmed that STAT5b, cyclin D1, and IGF-1R is
more » ... and IGF-1R is up-regulated by hypoxia, and the increased STAT5b binds strongly to the STAT5-binding sites contained within the distal 5'-flanking region of IGF-1 gene in breast cancer cells. EMSA studies showed that STAT5 binding activity to the IGF-1 and cyclin D1 promoter was distinctly decreased by hemin in STAT5b-transfected COS-7 or MDA-MB 231 cells. IGF-1 gene expression was also decreased by hemin in mammary epithelial cells. STAT5b expression was inhibited in siRNA experiments and by hemin, leading to decreased levels of IGF-1. These results provide a basis for molecular targets in cancer treatment via the STAT5b/IGF-1 or /cyclin D1 pathway in solid tumor cells. These data indicate that hemin inhibits the cyclin D1 and IGF-1 expression via STAT5b under hypoxia in ER·-negative breast cancer cells. These findings are valuable toward understanding the role of hemin-induced inhibition of cyclin D1 and IGF-1 expression under hypoxia in invasive and metastatic breast cancer. Abbreviations: STAT, signal transducers and activators of transcription; IGF-1, insulin-like growth factor-1; ER·, estrogen receptor-·; EMSA, electrophoretic mobility shift assay; GAS, IFN-Á-activated sequence; FAC, ferric ammonium citrate
doi:10.3892/ijo_00000608 fatcat:que645ra2ve2dlqyfzgy37zwj4