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A somatic mutation in the 5′UTR of BRCA1 gene in sporadic breast cancer causes down-modulation of translation efficiency

Oncogene volume 20, pages 4596–4600 (2001)Cite this article

Abstract

Mutations in the 5′ UTR which cause increment/decrement of translation efficiency have been recently described as a novel molecular mechanism of disease. Alterations in the consensus sequence for the translation initiation may promote context-dependent leaky scanning of ribosomes and/or initiation from a downstream AUG codon. Initiation of translation from a downstream in-frame AUG codon in BRCA1 gene was recently identified in normal cells and possibly in breast cancer. Here we present further insight into BRCA1 translational pathophysiology investigating the role of the canonical structure of the initiation consensus sequence of BRCA1. We have analysed the effect of a somatic point mutation (117 G>C) in position −3 with respect to the AUG of the BRCA1 gene, identified in a highly aggressive sporadic breast cancer. We constructed chimeric genes encoding the luciferase reporter sequence downstream of the wild type or the mutated BRCA1 5′UTR. These transcripts were tested for their activity in in vitro and in vivo systems. In in vitro transcription/translation assays the estimated translation efficiency of the construct with the mutated BRCA1 5′UTR was 30–50% lower than that with the wild type BRCA1 5′UTR. The same chimeric genes were analysed for their expression in vivo by transient transfection in human cells. While the two constructs were equally transcribed, the plasmid carrying the mutated sequence produced 70% less luciferase activity compared to the wild type sequence. Finally, to obtain a direct evaluation on translational efficiency in vivo, we analysed mRNA translation on translationally active and non-active ribosomes separated from transfected cells. Mutant mRNA was partially localized in subpolysomal particles analytically confirming a polysome recruitment defect. Thus, characterization of BRCA1 5′UTR and translation efficiency seems to provide new insight into BRCA1 role in breast and ovarian cancer pathogenesis.

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Acknowledgements

We thank Fabrizio Loreni for helpful and stimulating discussions, Paola Parrella for advice, Jill McMahon for critical reading of the manuscript; Marcello Giorgi for technical support. We are also grateful to Dr Bujard for providing pUHD cloning vector. This work was supported by grants from IRCCS Casa Sollievo della Sofferenza (FG), Ministero della Sanità, Ricerca Corrente 1998, and from C.N.R., Programma Biotecnologie, legge 95/96. E Signori was supported by fellowship from IRCCS Casa Sollievo della Sofferenza (FG).

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Authors and Affiliations

  1. Laboratory for Molecular Pathology and Gene Therapy, IRCCS H. Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, 71013, Italy

    Emanuela Signori, Sara Papa & Vito Michele Fazio

  2. Istituto di Neurobiologia e Medicina Molecolare, CNR, Area di Ricerca Tor Vergata, Rome, 00133, Italy

    Emanuela Signori, Monica Rinaldi & Vito Michele Fazio

  3. Dipartimento di Biologia, Università Tor Vergata, Rome, 00133, Italy

    Claudia Bagni, Beatrice Primerano & Francesco Amaldi

  4. Laboratory for Molecular Medicine and Biotechnology, Università Campus Bio-Medico, School of Medicine, Rome, 00155, Italy

    Monica Rinaldi & Vito Michele Fazio

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  1. Emanuela Signori
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  2. Claudia Bagni
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Correspondence to Vito Michele Fazio.

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Signori, E., Bagni, C., Papa, S. et al. A somatic mutation in the 5′UTR of BRCA1 gene in sporadic breast cancer causes down-modulation of translation efficiency. Oncogene 20, 4596–4600 (2001). https://doi.org/10.1038/sj.onc.1204620

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