Identification of Target Genes of the Steroid Hormone Receptor Co- Activator AIB1 (Amplified in Breast Cancer 1).

摘要

Steroid hormones play pivotal roles in the control of breast cancer proliferation and differentiation. The biological effects of these hormones are mediated through intracellular receptor proteins, e.g. the estrogen receptor (SR) and through interaction of these receptors with specific co-activators. Of particular interest is the co-activator AIB1 (amplified in breast cancer 1). The AIB1 gene was found to be amplified in 5-10% of primary breast tumor specimens and AIBl mRNA was found to be overexpressed in many breast tumor specimens. It has been shown that AIB1 promotes the activity of the ER and the growth of human MCF-7 breast cancer cells. Our hypothesis was that AIBl determines activation or repression of a vast number of genes important for breast cancer growth. Our goal in this study was to identify these target genes. We generated MCF-7 breast cancer cell lines in which we could specifically downregulate AIB1 levels utilizing tetracycline-regulatable ribozymes directed against AIBl. Utilizing these cells, we found, after estrogen and growth factor stimulation, that gene expression profiles differed significantly from cells with high AIBl levels when compared to cells with significantly reduced AIBl levels by microarray analysis. Several of the identified AIB1 target genes might have implications for breast cancer therapy.