Inhibition of breast cancer growth and invasion by single-minded 2s.
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 10-25 times 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.
Kwak
Hyeong-Il
HI
Department of Integrated Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843-4458, USA.
Gustafson
Tanya
T
Metz
Richard P
RP
Laffin
Brian
B
Schedin
Pepper
P
Porter
Weston W
WW
D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000502:physiology*; D045744:Cell Line, Tumor; D002891:Chromosomes, Human, Pair 21; D017931:DNA Primers; D018628:Gene Dosage; D006801:Humans; D019278:Matrix Metalloproteinase 3 / Q000235:genetics; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic
D051792:Basic Helix-Loop-Helix Proteins; D017931:DNA Primers; D019278:Matrix Metalloproteinase 3; C417032:SIM2 protein, human