Data from RIN1 Is a Breast Tumor Suppressor Gene

Abstract

<div>Abstract<p>Breast cancer progression is driven by altered gene expression. We show that the <i>RIN1</i> gene, which encodes a RAS effector regulating epithelial cell properties, is silenced in breast tumor cell lines compared with cultured human mammary epithelial cells. We also report that RIN1 is often reduced in human breast tumor cells compared with morphologically normal breast glandular cells. At least two silencing mechanisms seem to be involved. Overexpression of the transcription repressor <i>SNAI1</i> (Snail) was observed in ZR75-1 cells, and <i>SNAI1</i> knockdown restored <i>RIN1</i> expression. In addition, DNA methylation within the <i>RIN1</i> promoter and the first exon in KPL-1 cells suggested that epigenetic modifications may contribute to silencing, and demethylation was shown to restore RIN1 expression. Reexpression of <i>RIN1</i> was shown to inhibit anchorage-independent growth in soft agar. In addition, RIN1 expression inhibited both the initiation and progression of tumorigenesis for two breast tumor cell lines in a mouse model, consistent with a tumor suppressor function. We also show that RIN1 acts as a negative regulator of tumor cell invasive growth and that this requires the ABL kinase–signaling function of RIN1, suggesting a mechanism through which <i>RIN1</i> silencing may contribute to breast cancer progression. [Cancer Res 2007;67(24):11510–6]</p></div>