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

Abstract

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.

• Authors: Eun-Joung Lim, Youn-Hee Joung, Se-Mi Jung, Se Hyung Park, Jin Hee Park, Sang Yoon Kim, Tae Sook Hwang, Dae Young Hong, So Chung Chung, Sang-Kyu Ye, Eon-Soo Moon, Eui U Park, Taekyu Park, Ill-Min Chung, Young Mok Yang
• Journal: International journal of oncology (Int J Oncol) Vol. 36 Issue 5 Pg. 1243-51 (May 2010) ISSN: 1791-2423 [Electronic] Greece
• PMID: 20372799 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Estrogen Receptor alpha
• STAT5 Transcription Factor
• STAT5B protein, human
• Cyclin D1
• Insulin-Like Growth Factor I
• Hemin

Topics

• Animals
• CHO Cells
• COS Cells
• Cell Line, Tumor
• Chlorocebus aethiops
• Cricetinae
• Cricetulus
• Cyclin D1 (antagonists & inhibitors)
• Estrogen Receptor alpha (metabolism)
• Gene Expression Regulation, Neoplastic
• Hemin (chemistry, metabolism)
• Humans
• Hypoxia
• Insulin-Like Growth Factor I (antagonists & inhibitors)
• Neoplasm Invasiveness
• Neoplasm Metastasis
• STAT5 Transcription Factor (metabolism)