A cyclin D1/microRNA 17/20 regulatory feedback loop in control of breast cancer cell proliferation

Decreased expression of specific microRNAs (miRNAs) occurs in human tumors, which suggests a function for miRNAs in tumor suppression. Herein, levels of the miR-17-5p/miR-20a miRNA cluster were inversely correlated to cyclin D1 abundance in human breast tumors and cell lines. MiR-17/20 suppressed breast cancer cell proliferation and tumor colony formation by negatively regulating cyclin D1 translation via a conserved 3′ untranslated region miRNA-binding site, thereby inhibiting serum-induced S phase entry. The cell cycle effect of miR-17/20 was abrogated by cyclin D1 siRNA and in cyclin D1–deficient breast cancer cells. Mammary epithelial cell–targeted cyclin D1 expression induced miR-17-5p and miR-20a expression in vivo, and cyclin D1 bound the miR-17/20 cluster promoter regulatory region. In summary, these studies identify a novel cyclin D1/miR-17/20 regulatory feedback loop through which cyclin D1 induces miR-17-5p/miR-20a. In turn, miR-17/20 limits the proliferative function of cyclin D1, thus linking expression of a specific miRNA cluster to the regulation of oncogenesis.

[1]  Y. Yatabe,et al.  Reduced Expression of the let-7 MicroRNAs in Human Lung Cancers in Association with Shortened Postoperative Survival , 2004, Cancer Research.

[2]  C. Croce,et al.  MicroRNA signatures in human cancers , 2006, Nature Reviews Cancer.

[3]  C. Croce,et al.  Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[4]  W. Gerald,et al.  Endogenous human microRNAs that suppress breast cancer metastasis , 2008, Nature.

[5]  Mahadev Rao,et al.  Cyclin D1 Inhibits Peroxisome Proliferator-activated Receptor γ-mediated Adipogenesis through Histone Deacetylase Recruitment* , 2005, Journal of Biological Chemistry.

[6]  George P Cobb,et al.  microRNAs as oncogenes and tumor suppressors. , 2007, Developmental biology.

[7]  Muller Fabbri,et al.  A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. , 2005, The New England journal of medicine.

[8]  Lin Zhang,et al.  The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis , 2008, Nature Cell Biology.

[9]  S. Lowe,et al.  A microRNA polycistron as a potential human oncogene , 2005, Nature.

[10]  C. Croce,et al.  miR-15 and miR-16 induce apoptosis by targeting BCL2. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[11]  U. Kutay,et al.  Nuclear Export of MicroRNA Precursors , 2004, Science.

[12]  E. Lai.  Micro RNAs are complementary to 3′ UTR sequence motifs that mediate negative post-transcriptional regulation , 2002, Nature Genetics.

[13]  Anping Li,et al.  Cyclin D1 Regulates Cellular Migration through the Inhibition of Thrombospondin 1 and ROCK Signaling , 2006, Molecular and Cellular Biology.

[14]  Chang-Zheng Chen,et al.  MicroRNAs as oncogenes and tumor suppressors. , 2005, The New England journal of medicine.

[15]  Zuoren Yu,et al.  MicroRNA Mirn122a Reduces Expression of the Posttranscriptionally Regulated Germ Cell Transition Protein 2 (Tnp2) Messenger RNA (mRNA) by mRNA Cleavage1 , 2005, Biology of reproduction.

[16]  Y. Yatabe,et al.  A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. , 2005, Cancer research.

[17]  Guan-Tarn Huang,et al.  Loss of heterozygosity at chromosome 13q in hepatocellular carcinoma: identification of three independent regions. , 1999, European journal of cancer.

[18]  Anwar Hossain,et al.  Mir-17-5p Regulates Breast Cancer Cell Proliferation by Inhibiting Translation of AIB1 mRNA , 2006, Molecular and Cellular Biology.

[19]  K. Gunsalus,et al.  Combinatorial microRNA target predictions , 2005, Nature Genetics.

[20]  Michael Q. Zhang,et al.  Use of Chromatin Immunoprecipitation To Clone Novel E2F Target Promoters , 2001, Molecular and Cellular Biology.

[21]  C. Croce,et al.  An oligonucleotide microchip for genome-wide microRNA profiling in human and mouse tissues. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[22]  C. Albanese,et al.  Transforming p21ras Mutants and c-Ets-2 Activate the Cyclin D1 Promoter through Distinguishable Regions (*) , 1995, The Journal of Biological Chemistry.

[23]  Eric Westhof,et al.  Single Processing Center Models for Human Dicer and Bacterial RNase III , 2004, Cell.

[24]  V. Ambros.  The functions of animal microRNAs , 2004, Nature.

[25]  Emma Lees,et al.  Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice , 1994, Nature.

[26]  L. Lim,et al.  A microRNA component of the p53 tumour suppressor network , 2007, Nature.

[27]  Anwar Hossain,et al.  Mir-17-5 p Regulates Breast Cancer Cell Proliferation by Inhibiting Translation of AIB 1 mRNA , 2006 .

[28]  F. Slack,et al.  RAS Is Regulated by the let-7 MicroRNA Family , 2005, Cell.

[29]  C. Croce,et al.  miRNAs, Cancer, and Stem Cell Division , 2005, Cell.

[30]  F. Slack,et al.  Oncomirs — microRNAs with a role in cancer , 2006, Nature Reviews Cancer.

[31]  J. Gudmundsson,et al.  Mapping loss of heterozygosity at chromosome 13q: loss at 13q12-q13 is associated with breast tumour progression and poor prognosis. , 1998, European journal of cancer.

[32]  B. Cullen,et al.  Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. , 2003, Genes & development.

[33]  L. Augenlicht,et al.  Cyclin D1 Genetic Heterozygosity Regulates Colonic Epithelial Cell Differentiation and Tumor Number in ApcMin Mice , 2004, Molecular and Cellular Biology.

[34]  Y. Geng,et al.  Specific protection against breast cancers by cyclin D1 ablation , 2001, Nature.

[35]  B. Cullen.  Transcription and processing of human microRNA precursors. , 2004, Molecular cell.

[36]  Kathryn A. O’Donnell,et al.  c-Myc-regulated microRNAs modulate E2F1 expression , 2005, Nature.

[37]  C. Croce,et al.  Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Itaru Matsumura,et al.  E2F1 and c-Myc in Cell Growth and Death , 2003, Cell cycle.

[39]  Lawrence A. Donehower,et al.  Cyclin D1 Repression of Peroxisome Proliferator-Activated Receptor γ Expression and Transactivation , 2003, Molecular and Cellular Biology.

[40]  Carlo M. Croce,et al.  MicroRNAs 17-5p–20a–106a control monocytopoiesis through AML1 targeting and M-CSF receptor upregulation , 2007, Nature Cell Biology.

[41]  Vincent De Guire,et al.  An E2F/miR-20a Autoregulatory Feedback Loop* , 2007, Journal of Biological Chemistry.

[42]  Y. Yarden,et al.  Cyclin D1 Is Required for Transformation by Activated Neu and Is Induced through an E2F-Dependent Signaling Pathway , 2000, Molecular and Cellular Biology.

[43]  L. Augenlicht,et al.  Cyclin D1 Genetic Heterozygosity Regulates Colonic Epithelial Cell Differentiation and Tumor Number in ApcMin Mice , 2005, Molecular and Cellular Biology.

[44]  林下 陽二.  A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation , 2006 .

[45]  Chenguang Wang,et al.  Minireview: Cyclin D1: normal and abnormal functions. , 2004, Endocrinology.