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Metastatic lymph node 64 (MLN64), a gene overexpressed in breast cancers, is regulated by Sp/KLF transcription factors

Oncogene volume 22, pages 3770–3780 (2003)Cite this article

Abstract

MLN64, is invariably coamplified and coexpressed with erbB-2 in breast cancers. The human MLN64 and ERBB2 genes are positioned at less than 50 kb from each other, on chromosome 17q12. To understand the molecular basis of MLN64 overexpression in cancer, the genomic region containing the MLN64 and ERBB2 genes was isolated and mapped. The two genes, DARPP32 and Telethonin, flanking MLN64 respectively on its centromeric and telomeric sides, although coamplified, are not overexpressed in breast cancer cells, indicating that geneamplification is not sufficient to allow overexpression. The MLN64 minimal promoter was isolated and found to be a housekeeping gene promoter containing four potential Sp1 binding elements. Using Sp1-deficient Drosophila SL2 cells, MLN64 promoter activity was induced in a dose-dependent manner by exogenous Sp1 addition. Furthermore, mutation of each individual Sp1 element resulted in a significant decrease in reporter gene activity, indicating that all the Sp1 binding elements are functional and act together to promote gene expression. Since the ERBB2 promoter is also positively regulated by Sp1, this study indicates that MLN64 and ERBB2 genes share common transcriptional controls together with a physical link on chromosome 17q. We speculate that, in addition to the oncogenic potential of erbB-2 overexpression, the unbalanced action of MLN64 contributes to the poor clinical outcome of breast tumors bearing this amplified region.

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Acknowledgements

We thank S Chan and E Lalli for critical reading of the manuscript; C Wendling, S Vicaire, F Ruffenach, I Colas and E Troesh for technical assistance. FA was a recipient of an Association pour la Recherche sur le Cancer (ARC) fellowship and SD was a recipient of an allocation du Ministere de l'Education Nationale et de la Recherche et de la Technologie. This work was supported by a special fund from the Ligue Nationale Francaise Contre le Cancer (LNCC, équipe labellisée) and by funds from the Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), L'Hôpital Universitaire de Strasbourg and the LNCC comités du Haut-Rhin et du Bas-Rhin.

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  1. Anne Boulay

    Present address: Novartis Pharma AG, Klibeckstrasse VKL 125.3.16, 4002, Basel, Switzerland

  2. Christel Moog-Lutz

    Present address: U440 INSERM/ IFM, 17, rue du Fer à Moulin, 75005, Paris, France

Authors and Affiliations

  1. Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS/INSERM/Université Louis Pasteur, BP 10142, 67404 Illkirch, C.U. de Strasbourg, France

    Fabien Alpy, Anne Boulay, Christel Moog-Lutz, Kumari L Andarawewa, Sébastien Degot, Isabelle Stoll, Marie-Christine Rio & Catherine Tomasetto

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  1. Fabien Alpy
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Correspondence to Catherine Tomasetto.

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Alpy, F., Boulay, A., Moog-Lutz, C. et al. Metastatic lymph node 64 (MLN64), a gene overexpressed in breast cancers, is regulated by Sp/KLF transcription factors. Oncogene 22, 3770–3780 (2003). https://doi.org/10.1038/sj.onc.1206500

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