Hemin inhibits cyclin D1 and IGF-1 expression via STAT5b under hypoxia in ERalpha-negative MDA-MB 231 breast cancer cells.
Cyclin D1 and insulin-like growth factor 1 receptor (IGF-1R) 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 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 ERalpha-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.
Lim
Eun-Joung
EJ
Department of Pathology, School of Medicine, and Institute of Biomedical Science and Technology, Konkuk University, Seoul 143-701, Korea.
Joung
Youn-Hee
YH
Jung
Se-Mi
SM
Park
Se Hyung
SH
Park
Jin Hee
JH
Kim
Sang Yoon
SY
Hwang
Tae Sook
TS
Hong
Dae Young
DY
Chung
So Chung
SC
Ye
Sang-Kyu
SK
Moon
Eon-Soo
ES
Park
Eui U
EU
Park
Taekyu
T
Chung
Ill-Min
IM
Yang
Young Mok
YM
D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D019938:Cyclin D1 / Q000037:antagonists & inhibitors*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006427:Hemin / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D050799:STAT5 Transcription Factor / Q000378:metabolism*
D047628:Estrogen Receptor alpha; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; D019938:Cyclin D1; D007334:Insulin-Like Growth Factor I; D006427:Hemin