Carcinogenesis Advance Access originally published online on July 13, 2006
Carcinogenesis 2007 28(2):259-266; doi:10.1093/carcin/bgl122
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Inhibition of breast cancer growth and invasion by single-minded 2s
1 Department of Integrated Biosciences, College of Veterinary Medicine Texas A&M University, College Station, TX 77843-4458, USA
2 Division of Medical Oncology, University of Colorado Health Sciences Center CO, USA
*To whom correspondence and requests for reprints should be addressed. Tel: +979 845 0733; Fax: +979 862 4929; Email: wporter{at}cvm.tamu.edu
Single-minded 2 (SIM2) is a member of the bHLH-PAS family of transcription factors. SIM2 was initially identified by positional cloning on chromosome 21 and is thought to contribute to the etiology of trisomy-21 [Down syndrome (DS)]. In addition to the physical and mental deficiencies associated with this genetic disease, it has become apparent that women with DS are 10–25times less likely to die from breast cancer in comparison with age-matched normal populations. This is thought to be a result of gene dosage effect of tumor suppressor genes on chromosome 21. Here, we report that a splice variant of SIM2, SIM2 short (SIM2s), is differentially expressed in normal breast and breast cancer-derived cell lines and is downregulated in human breast cancer samples. Re-establishment of SIM2s in MDA-MB-435 breast cancer cells significantly reduced proliferation, anchorage-independent growth and invasive potential. Consistent with its role as a transcriptional repressor, SIM2s directly decreased expression of matrix metalloprotease-3, a known mediator of breast cancer metastasis. These results suggest that SIM2s has breast tumor suppressive activity.
Abbreviations: bHLH, basic helix–loop–helix; CAV1, caveolin-1; ChIP, chromatin immunoprecipitation; DS, Down syndrome; ECM, extracellular matrix; MMP, matrix metalloproteases; PAS, Per-Arnt-SIM; PMA, phorbol 12-myristate 13-acetate; RT–PCR, reverse transcription–polymerase chain reaction; SE, standard error; SIM2, single-minded 2; SIM2s, SIM2 short
Received March 1, 2006; revised June 26, 2006; accepted June 30, 2006.
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