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RIN1 Is a Breast Tumor Suppressor Gene

Departments of ¹ Biological Chemistry, ² Medicine, and ³ Pathology and Laboratory Medicine, ⁴ Jonsson Comprehensive Cancer Center, and ⁵ Molecular Biology Institute, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California

Requests for reprints: John Colicelli, Department of Biological Chemistry, University of California at Los Angeles Jonsson Cancer Center, 33-257 Center for Health Sciences, 10833 Le Conte Avenue, Los Angeles, CA 90095. Phone: 310-625-5272; Fax: 310-206-5272; E-mail: colicelli{at}mednet.ucla.edu.

Breast cancer progression is driven by altered gene expression. We show that the RIN1 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 SNAI1 (Snail) was observed in ZR75-1 cells, and SNAI1 knockdown restored RIN1 expression. In addition, DNA methylation within the RIN1 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 RIN1 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 RIN1 silencing may contribute to breast cancer progression. [Cancer Res 2007;67(24):11510–6]

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