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.

[1]  R. Narayanan,et al.  Identification of Down's syndrome critical locus gene SIM2-s as a drug therapy target for solid tumors , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[2]  M. Loda,et al.  Caveolin-1 promotes tumor progression in an autochthonous mouse model of prostate cancer: genetic ablation of Cav-1 delays advanced prostate tumor development in tramp mice. , 2005, The Journal of biological chemistry.

[3]  J. Merrick,et al.  Cancer incidence in persons with Down syndrome in Israel. , 2002, Down's syndrome, research and practice : the journal of the Sarah Duffen Centre.

[4]  J. Pelletier,et al.  Characterization of msim, a murine homologue of the Drosophila sim transcription factor. , 1996, Genomics.

[5]  J. Hogenesch,et al.  The PAS superfamily: sensors of environmental and developmental signals. , 2000, Annual review of pharmacology and toxicology.

[6]  H. Hasle,et al.  [Incidence of cancer in individuals with Down syndrome]. , 2000, Tidsskrift for Den Norske Laegeforening.

[7]  Massimo Loda,et al.  Caveolin-1 Promotes Tumor Progression in an Autochthonous Mouse Model of Prostate Cancer , 2005, Journal of Biological Chemistry.

[8]  M. Lisanti,et al.  Caveolin-1 in oncogenic transformation, cancer, and metastasis. , 2005, American journal of physiology. Cell physiology.

[9]  Ming You,et al.  Wildtype Kras2 can inhibit lung carcinogenesis in mice , 2001, Nature Genetics.

[10]  H. Hasle,et al.  Risks of leukaemia and solid tumours in individuals with Down's syndrome , 2000, The Lancet.

[11]  M. Passos-Bueno,et al.  High serum endostatin levels in Down syndrome: implications for improved treatment and prevention of solid tumours , 2001, European Journal of Human Genetics.

[12]  Z. Werb,et al.  Targeted expression of stromelysin-1 in mammary gland provides evidence for a role of proteinases in branching morphogenesis and the requirement for an intact basement membrane for tissue-specific gene expression [published erratum appears in J Cell Biol 1996 Feb;132(4):following 752] , 1994, The Journal of cell biology.

[13]  Patricia Keating,et al.  Inhibition of Single Minded 2 gene expression mediates tumor-selective apoptosis and differentiation in human colon cancer cells. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[14]  L. Matrisian,et al.  TEL, a Putative Tumor Suppressor, Modulates Cell Growth and Cell Morphology of Ras-Transformed Cells While Repressing the Transcription of stromelysin-1 , 2000, Molecular and Cellular Biology.

[15]  R. Narayanan,et al.  Down's syndrome-associated single minded gene as a novel tumor marker. , 2002, Anticancer Research.

[16]  Carole Mathelin,et al.  Dual stromelysin-3 function during natural mouse mammary tumor virus-ras tumor progression. , 2003, Cancer research.

[17]  T. Golub,et al.  The Six 1 homeoprotein stimulates tumorigenesis by reactivation of cyclin A 1 , 2004 .

[18]  R. Narayanan,et al.  Down's syndrome-associated Single Minded 2 gene as a pancreatic cancer drug therapy target. , 2003, Cancer letters.

[19]  H. Moon,et al.  Overexpression of membrane-type matrix metalloproteinase-1 gene induces mammary gland abnormalities and adenocarcinoma in transgenic mice. , 2001, Cancer research.

[20]  J. Nelson,et al.  Caveolin expression is decreased following androgen deprivation in human prostate cancer cell lines , 1999, The Prostate.

[21]  S. Antonarakis,et al.  Mice trisomic for a bacterial artificial chromosome with the single-minded 2 gene (Sim2) show phenotypes similar to some of those present in the partial trisomy 16 mouse models of Down syndrome. , 2000, Human molecular genetics.

[22]  K. Miyazaki,et al.  Snail and SIP1 increase cancer invasion by upregulating MMP family in hepatocellular carcinoma cells , 2004, British Journal of Cancer.

[23]  Takahide Kohro,et al.  Vascular Endothelial Growth Factor- and Thrombin-induced Termination Factor, Down Syndrome Critical Region-1, Attenuates Endothelial Cell Proliferation and Angiogenesis*♦ , 2004, Journal of Biological Chemistry.

[24]  M. Sundaram,et al.  The love-hate relationship between Ras and Notch. , 2005, Genes & development.

[25]  G. Murphy,et al.  Functional Significance of MMP-9 in Tumor Necrosis Factor-Induced Proliferation and Branching Morphogenesis of Mammary Epithelial Cells. , 2000, Endocrinology.

[26]  V. Band,et al.  Loss of p53 protein in human papillomavirus type 16 E6-immortalized human mammary epithelial cells , 1991, Journal of virology.

[27]  A. Sasco,et al.  An excess of testicular germ cell tumors in down's syndrome , 1997, Cancer.

[28]  M. Duffy,et al.  Ets2 transcription factor in normal and neoplastic human breast tissue. , 2006, European journal of cancer.

[29]  T. Golub,et al.  The Six1 homeoprotein stimulates tumorigenesis by reactivation of cyclin A1. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[30]  D. Lovett,et al.  Tumour metastasis suppressor, nm23-beta, inhibits gelatinase A transcription by interference with transactivator Y-box protein-1 (YB-1). , 2002, The Biochemical journal.

[31]  O. Gotoh,et al.  cDNA cloning of a murine homologue of Drosophila single-minded, its mRNA expression in mouse development, and chromosome localization. , 1996, Biochemical and biophysical research communications.

[32]  B. Modan,et al.  Incidence of leukemia and other cancers in Down syndrome subjects in Israel , 2001, International journal of cancer.

[33]  Z. Werb,et al.  Mammary gland tumor formation in transgenic mice overexpressing stromelysin-1. , 1995, Seminars in cancer biology.

[34]  John N. Hutchinson,et al.  Caveolin-1 Gene Disruption Promotes Mammary Tumorigenesis and Dramatically Enhances Lung Metastasis in Vivo , 2004, Journal of Biological Chemistry.

[35]  J. Pelletier,et al.  The murine Sim-2 gene product inhibits transcription by active repression and functional interference , 1997, Molecular and cellular biology.

[36]  Z. Werb,et al.  Stromelysin-1 Regulates Adipogenesis during Mammary Gland Involution , 2001, The Journal of cell biology.

[37]  M. Barbacid,et al.  RAS oncogenes: the first 30 years , 2003, Nature Reviews Cancer.

[38]  Hans Clevers,et al.  Notch1 functions as a tumor suppressor in mouse skin , 2003, Nature Genetics.

[39]  Edgar D Staren,et al.  Matrix metalloproteinase expression in breast cancer. , 2003, The Journal of surgical research.

[40]  R. Metz,et al.  Differential Transcriptional Regulation by Mouse Single-minded 2s* , 2006, Journal of Biological Chemistry.

[41]  S. Chakraborti,et al.  Regulation of matrix metalloproteinases: An overview , 2003, Molecular and Cellular Biochemistry.

[42]  Sven Cnattingius,et al.  Mortality and cancer incidence among individuals with Down syndrome. , 2003, Archives of internal medicine.

[43]  G. Dotto,et al.  High commitment of embryonic keratinocytes to terminal differentiation through a Notch1-caspase 3 regulatory mechanism. , 2004, Developmental cell.

[44]  M. Lupien,et al.  Tumorigenesis and Neoplastic Progression Overexpression of Activated Murine Notch 1 and Notch 3 in Transgenic Mice Blocks Mammary Gland Development and Induces Mammary Tumors , 2022 .

[45]  R. Arceci,et al.  Mutations in GATA1 in both transient myeloproliferative disorder and acute megakaryoblastic leukemia of Down syndrome. , 2003, Blood cells, molecules & diseases.

[46]  Bing Zhang,et al.  Presence of the Acute Phase Protein, Bikunin, in the Endometrium of Gilts During Estrous Cycle and Early Pregnancy1 , 2001, Biology of reproduction.

[47]  M. L. Beau,et al.  Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome , 2002, Nature Genetics.

[48]  A. Sasco,et al.  Another reason to look for tumor suppressor genes on chromosome 21 , 1998, Genes, chromosomes & cancer.

[49]  三好 篤.  Snail accelerates cancer invasion by upregulating MMP expression and is associated with poor prognosis of hepatocellular carcinoma , 2005 .

[50]  S. Antonarakis,et al.  Cloning of two human homologs of the Drosophila single-minded gene SIM1 on chromosome 6q and SIM2 on 21q within the Down syndrome chromosomal region. , 1997, Genome research.

[51]  J. Connolly,et al.  Tumor progression in four mammary epithelial cell lines derived from the same patient. , 1990, Cancer research.

[52]  V. Cavaillès,et al.  Estrogen receptor cofactors expression in breast and endometrial human cancer cells , 1999, Molecular and Cellular Endocrinology.

[53]  D. Satgé,et al.  Down's syndrome protects against breast cancer: Is a constitutional cell microenvironment the key? , 2005, International journal of cancer.

[54]  M. Katsuki,et al.  Mild impairment of learning and memory in mice overexpressing the mSim2 gene located on chromosome 16: an animal model of Down's syndrome. , 1999, Human molecular genetics.

[55]  I. Pucci‐Minafra,et al.  Zymographic detection and clinical correlations of MMP-2 and MMP-9 in breast cancer sera , 2004, British Journal of Cancer.

[56]  R. Perez-soler,et al.  Complex effects of Ras proto-oncogenes in tumorigenesis. , 2003, Carcinogenesis.

[57]  M. Duffy,et al.  Overexpression of the Ets-1 transcription factor in human breast cancer , 2004, British Journal of Cancer.