RIN1 Is a Breast Tumor Suppressor Gene
Open Access
- 15 December 2007
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 67 (24), 11510-11516
- https://doi.org/10.1158/0008-5472.can-07-1147
Abstract
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]Keywords
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This publication has 46 references indexed in Scilit:
- The Tumor Metastasis Suppressor Gene Drg-1 Down-regulates the Expression of Activating Transcription Factor 3 in Prostate CancerCancer Research, 2006
- Breast Cancer Metastasis Suppressor 1 Functions as a Corepressor by Enhancing Histone Deacetylase 1-Mediated Deacetylation of RelA/p65 and Promoting ApoptosisMolecular and Cellular Biology, 2006
- Epigenetic gene silencing in cancer – a mechanism for early oncogenic pathway addiction?Nature Reviews Cancer, 2006
- The RASSF1A Tumor Suppressor Activates Bax via MOAP-1Online Journal of Public Health Informatics, 2006
- The transcriptional repressor Snail promotes mammary tumor recurrenceCancer Cell, 2005
- The Src Homology 2 Domain of Rin1 Mediates Its Binding to the Epidermal Growth Factor Receptor and Regulates Receptor EndocytosisOnline Journal of Public Health Informatics, 2003
- The Pro-apoptotic Ras Effector Nore1 May Serve as a Ras-regulated Tumor Suppressor in the LungOnline Journal of Public Health Informatics, 2003
- Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomasNature Genetics, 2002
- The transcription factor Snail controls epithelial–mesenchymal transitions by repressing E-cadherin expressionNature, 2000
- The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cellsNature, 2000