Implication of snoRNA U50 in human breast cancer.

Deletion of chromosome 6q is frequent in breast cancer, and the deletion often involves a region in 6q14-q16. At present, however, the underlying tumor suppressor gene has not been established. Based on a recent study identifying snoRNA U50 as a candidate for the 6q14-16 tumor suppressor gene in prostate cancer, we investigated whether U50 is also involved in breast cancer. PCR-based approaches showed that U50 underwent frequent genomic deletion and transcriptional downregulation in cell lines derived from breast cancer. Mutation screening identified the same 2-bp deletion of U50 as in prostate cancer in both cell lines and primary tumors from breast cancer, and the deletion was both somatic and in germline. Genotyping of a cohort of breast cancer cases and controls for the mutation demonstrated that, while homozygous genotype of the mutation was rare, its heterozygous genotype occurred more frequently in women with breast cancer. Functionally, re-expression of U50 resulted in the inhibition of colony formation in breast cancer cell lines. These results suggest that noncoding snoRNA U50 plays a role in the development and/or progression of breast cancer.

[1]  A. Rosenthal,et al.  SASH1: a candidate tumor suppressor gene on chromosome 6q24.3 is downregulated in breast cancer , 2003, Oncogene.

[2]  Wonshik Han,et al.  Genomic alterations identified by array comparative genomic hybridization as prognostic markers in tamoxifen-treated estrogen receptor-positive breast cancer , 2006, BMC Cancer.

[3]  P. Gregersen,et al.  Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33 , 2008, Proceedings of the National Academy of Sciences.

[4]  Frequent loss of heterozygosity on chromosome 6 in human ovarian carcinoma. , 1993, British journal of cancer.

[5]  R. Vessella,et al.  FOXO1A is a candidate for the 13q14 tumor suppressor gene inhibiting androgen receptor signaling in prostate cancer. , 2006, Cancer research.

[6]  A. Marchetti,et al.  Multiple regions of chromosome 6q affected by loss of heterozygosity in primary human breast carcinomas. , 1996, British Journal of Cancer.

[7]  H. Frierson,et al.  Deletion at 13q21 is associated with aggressive prostate cancers. , 2000, Cancer research.

[8]  F. Apiou,et al.  hZAC encodes a zinc finger protein with antiproliferative properties and maps to a chromosomal region frequently lost in cancer. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[9]  K. Winzer,et al.  A defined chromosome 6q fragment (at D6S310) harbors a putative tumor suppressor gene for breast cancer. , 1996, Oncogene.

[10]  I. Petersen,et al.  Chromosome alterations in breast carcinomas: frequent involvement of DNA losses including chromosomes 4q and 21q. , 1998, British Journal of Cancer.

[11]  J. Mattick.  RNA regulation: a new genetics? , 2004, Nature Reviews Genetics.

[12]  Robert A Smith,et al.  Cancer Screening in the United States, 2007: A Review of Current Guidelines, Practices, and Prospects , 2007, CA: a cancer journal for clinicians.

[13]  A. Causse,et al.  At least five regions of imbalance on 6q in breast tumors, combining losses and gains , 2000, Genes, chromosomes & cancer.

[14]  J. H. Lee,et al.  Frequent loss of heterozygosity on chromosomes 6q, 11, and 17 in human ovarian carcinomas. , 1990, Cancer research.

[15]  R. Terns,et al.  Non-coding RNAs: lessons from the small nuclear and small nucleolar RNAs , 2007, Nature Reviews Molecular Cell Biology.

[16]  P. Cairns,et al.  LOT1 (PLAGL1/ZAC1), the Candidate Tumor Suppressor Gene at Chromosome 6q24–25, Is Epigenetically Regulated in Cancer* , 2003, The Journal of Biological Chemistry.

[17]  R. Athwal,et al.  A gene on 6q 14-21 restores senescence to immortal ovarian tumor cells. , 1996, Oncogene.

[18]  H. Saya,et al.  Molecular analysis of the h-warts/LATS1 gene in human breast cancer. , 2000, International journal of oncology.

[19]  Yutaka Miura,et al.  Frequent somatic mutations of the transcription factor ATBF1 in human prostate cancer , 2005, Nature Genetics.

[20]  R. Schlenk,et al.  Clinical relevance of genomic aberrations in homogeneously treated high‐risk stage II/III breast cancer patients , 2001, International journal of cancer.

[21]  B. Dutrillaux,et al.  Characterization of chromosomal anomalies in human breast cancer. A comparison of 30 paradiploid cases with few chromosome changes. , 1990, Cancer genetics and cytogenetics.

[22]  J. Steitz,et al.  Classification of gas5 as a Multi-Small-Nucleolar-RNA (snoRNA) Host Gene and a Member of the 5′-Terminal Oligopyrimidine Gene Family Reveals Common Features of snoRNA Host Genes , 1998, Molecular and Cellular Biology.

[23]  C. Croce,et al.  Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25–q27 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[24]  B Johansson,et al.  Chromosomal imbalance maps of malignant solid tumors: a cytogenetic survey of 3185 neoplasms. , 1997, Cancer research.

[25]  R. Callahan,et al.  Mutations in human breast cancer: an overview. , 1989, Journal of the National Cancer Institute.

[26]  M. Mourtada-Maarabouni,et al.  GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer , 2009, Oncogene.

[27]  R. Siebert,et al.  Detection of 6q deletions in breast carcinoma cell lines by fluorescence in situ hybridization , 1998, Human Genetics.

[28]  P L Pearson,et al.  Allelotype of human breast carcinoma: a second major site for loss of heterozygosity is on chromosome 6q. , 1991, Oncogene.

[29]  J. Molès,et al.  The Candidate Tumor Suppressor Gene ZAC Is Involved in Keratinocyte Differentiation and Its Expression Is Lost in Basal Cell Carcinomas , 2005, Molecular Cancer Research.

[30]  W. Wang,et al.  UTRN on chromosome 6q24 is mutated in multiple tumors , 2007, Oncogene.

[31]  M. Urioste,et al.  Genome-wide linkage scan reveals three putative breast-cancer-susceptibility loci. , 2009, American journal of human genetics.

[32]  J. Mattick,et al.  Small regulatory RNAs in mammals. , 2005, Human molecular genetics.

[33]  Jin-Tang Dong.  Chromosomal Deletions and Tumor Suppressor Genes in Prostate Cancer , 2004, Cancer and Metastasis Reviews.

[34]  K Autio,et al.  DNA copy number losses in human neoplasms. , 1999, The American journal of pathology.

[35]  C. Theillet,et al.  Loss of heterozygosity on the long arm of chromosome 6 in breast cancer: possibly four regions of deletion. , 1996, Clinical cancer research : an official journal of the American Association for Cancer Research.

[36]  A. Kibel,et al.  SnoRNA U50 is a candidate tumor-suppressor gene at 6q14.3 with a mutation associated with clinically significant prostate cancer. , 2007, Human molecular genetics.

[37]  S. Stamm,et al.  The snoRNA HBII-52 Regulates Alternative Splicing of the Serotonin Receptor 2C , 2006, Science.