MicroRNA-mediated inhibition of prostate-derived Ets factor messenger RNA translation affects prostate-derived Ets factor regulatory networks in human breast cancer.

Prostate-derived Ets factor (PDEF) is an ETS transcription factor expressed in normal tissues with high epithelial cell content and noninvasive breast cancer cells. A putative tumor suppressor PDEF protein expression is often lost during progression to a more invasive phenotype. Interestingly, PDEF mRNA has been found to be retained or even overexpressed in the absence of protein; however, the mechanisms for this remain to be elucidated. This study identifies two microRNAs (miRNA) that directly act on and repress PDEF mRNA translation, leading to the loss of PDEF protein expression and the gain of phenotypes associated with invasive cells. In addition, we show that these miRNAs are elevated in human breast tumor samples. Together, these data describe a mechanism of regulation that explains, for the first time, the lack of correlation between PDEF mRNA and protein levels, providing insight into the underexplored role of posttranscriptional regulation and how this contributes to dysregulated protein expression in cancer. These observations have critical implications for therapeutically targeting miRNAs that contribute to cancer progression.

[1]  W. Isaacs,et al.  DD3: a new prostate-specific gene, highly overexpressed in prostate cancer. , 1999, Cancer research.

[2]  T. Libermann,et al.  PDEF, a Novel Prostate Epithelium-specific Ets Transcription Factor, Interacts with the Androgen Receptor and Activates Prostate-specific Antigen Gene Expression* , 2000, The Journal of Biological Chemistry.

[3]  T. Miki,et al.  Prostate-specific transcription factor hPSE is translated only in normal prostate epithelial cells. , 2000, Cancer research.

[4]  A. Hill,et al.  Prostate-Specific Ets (PSE) factor: a novel marker for detection of metastatic breast cancer in axillary lymph nodes , 2002, British Journal of Cancer.

[5]  E. Fearon,et al.  The SLUG zinc-finger protein represses E-cadherin in breast cancer. , 2002, Cancer research.

[6]  V. Sementchenko,et al.  Pdef expression in human breast cancer is correlated with invasive potential and altered gene expression. , 2003, Cancer research.

[7]  H. Moses,et al.  Induction by transforming growth factor-β1 of epithelial to mesenchymal transition is a rare event in vitro , 2004, Breast Cancer Research.

[8]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[9]  N. Brünner,et al.  Expression of c-ets-1 mRNA is associated with an invasive, EMT-derived phenotype in breast carcinoma cell lines , 1997, Clinical & Experimental Metastasis.

[10]  E. Madrigal-Bujaidar,et al.  Short communication Identification of chromosomal changes with comparative genomic hybridization in sporadic breast cancer in Mexican women , 2004 .

[11]  F. Portillo,et al.  Transcriptional regulation of cadherins during development and carcinogenesis. , 2004, The International journal of developmental biology.

[12]  R. Orr,et al.  Molecular Detection of Micrometastatic Breast Cancer in Histopathology-Negative Axillary Lymph Nodes Correlates With Traditional Predictors of Prognosis: An Interim Analysis of a Prospective Multi-Institutional Cohort Study , 2004, Annals of surgery.

[13]  A. Seth,et al.  ETS transcription factors and their emerging roles in human cancer. , 2005, European journal of cancer.

[14]  Michael T. McManus,et al.  The microRNA miR-196 acts upstream of Hoxb8 and Shh in limb development , 2005, Nature.

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

[16]  Jiri Zavadil,et al.  TGF-β and epithelial-to-mesenchymal transitions , 2005, Oncogene.

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

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

[19]  H. Horvitz,et al.  MicroRNA expression profiles classify human cancers , 2005, Nature.

[20]  J. Zavadil,et al.  TGF-beta and epithelial-to-mesenchymal transitions. , 2005, Oncogene.

[21]  J. Russo,et al.  Detection of chromosomal aberrations by comparative genomic hybridization during transformation of human breast epithelial cells in vitro. , 2006, International journal of oncology.

[22]  C. Croce,et al.  A microRNA expression signature of human solid tumors defines cancer gene targets , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[23]  R. Stephens,et al.  Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. , 2006, Cancer cell.

[24]  Yan Li,et al.  MicroRNA-9a ensures the precise specification of sensory organ precursors in Drosophila. , 2006, Genes & development.

[25]  C. Croce,et al.  MicroRNA expression and function in cancer. , 2006, Trends in molecular medicine.

[26]  Fengzhi Li,et al.  Prostate-derived Ets transcription factor (PDEF) downregulates survivin expression and inhibits breast cancer cell growth in vitro and xenograft tumor formation in vivo , 2007, Breast Cancer Research and Treatment.

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

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

[29]  N. Rajewsky.  microRNA target predictions in animals , 2006, Nature Genetics.

[30]  C. Benz,et al.  Optimized high-throughput microRNA expression profiling provides novel biomarker assessment of clinical prostate and breast cancer biopsies , 2006, Molecular Cancer.

[31]  Wen-Lin Kuo,et al.  A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. , 2006, Cancer cell.

[32]  C. Sen,et al.  MicroRNA in cutaneous wound healing: a new paradigm. , 2007, DNA and cell biology.

[33]  R. Weinberg,et al.  Tumour invasion and metastasis initiated by microRNA-10b in breast cancer , 2007, Nature.

[34]  M. Bhasin,et al.  Reduced PDEF expression increases invasion and expression of mesenchymal genes in prostate cancer cells. , 2007, Cancer research.

[35]  N. Rajewsky,et al.  The evolution of gene regulation by transcription factors and microRNAs , 2007, Nature Reviews Genetics.

[36]  J. Steitz,et al.  Target mRNAs are repressed as efficiently by microRNA-binding sites in the 5′ UTR as in the 3′ UTR , 2007, Proceedings of the National Academy of Sciences.

[37]  Grace X. Y. Zheng,et al.  Dynamic regulation of miRNA expression in ordered stages of cellular development. , 2007, Genes & development.

[38]  David P Turner,et al.  Prostate-derived ETS factor is a mediator of metastatic potential through the inhibition of migration and invasion in breast cancer. , 2007, Cancer research.

[39]  Carlos Caldas,et al.  MicroRNA expression profiling of human breast cancer identifies new markers of tumour subtype , 2007 .

[40]  Leonard D. Goldstein,et al.  MicroRNA expression profiling of human breast cancer identifies new markers of tumor subtype , 2007, Genome Biology.

[41]  Yang Wang,et al.  MicroRNA: past and present. , 2007, Frontiers in bioscience : a journal and virtual library.

[42]  David P Turner,et al.  Defining ETS transcription regulatory networks and their contribution to breast cancer progression , 2007, Journal of cellular biochemistry.

[43]  J. Zavadil,et al.  Transforming Growth Factor-β and microRNA:mRNA Regulatory Networks in Epithelial Plasticity , 2007, Cells Tissues Organs.

[44]  E. Wiemer.  The role of microRNAs in cancer: no small matter. , 2007, European journal of cancer.