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p63/MT1-MMP axis is required for in situ to invasive transition in basal-like breast cancer

Oncogene volume 35, pages 344–357 (2016)Cite this article

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Abstract

The transition of ductal carcinoma in situ (DCIS) to invasive breast carcinoma requires tumor cells to cross the basement membrane (BM). However, mechanisms underlying BM transmigration are poorly understood. Here, we report that expression of membrane-type 1 (MT1)-matrix metalloproteinase (MMP), a key component of the BM invasion program, increases during breast cancer progression at the in situ to invasive breast carcinoma transition. In the intraductal xenograft model, MT1-MMP is required for BM transmigration of MCF10DCIS.com breast adenocarcinoma cells and is overexpressed in cell clusters overlying focal BM disruptions and at the invasive tumor front. Mirrored upregulation of p63 and MT1-MMP is observed at the edge of MCF10DCIS.com xenograft tumors and p63 is required for induction of MT1-MMP-dependent invasive program in response to microenvironmental signals. Immunohistochemistry and analysis of public database reveal that p63 and MT1-MMP are upregulated in human basal-like breast tumors suggesting that p63/MT1-MMP axis contributes to progression of basal-like breast cancers with elevated p63 and MT1-MMP levels.

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Acknowledgements

We acknowledge the Breast Cancer Study Group and patients of Institut Curie for the breast tumor samples, Dr G Scita for critical reading of the manuscript, the Nikon Imaging Centre @ Institut Curie-CNRS and Cell and Tissue Imaging Facility of Institut Curie for help with image acquisition, V Dangles-Marie and MA Deugnier for help with the intraductal xenograft model, K Lehti, GP Dotto, C Albiges-Rizo and O Destaing for providing reagents, D Gentien for the gift of breast tumor cell line mRNA samples and M Sefta for correlation analysis of MT1-MMP and p63 expression in breast tumor cell lines. CL was supported by grants from Agence Nationale pour la Recherche and Fondation Pierre-Gilles de Gennes pour la Recherche, EI by a grant from Région Ile-de-France, AG by a grant from Appel à Projet 'Biologie des Systèmes' 2012 du Plan cancer 2009–2013 (INVADE project) and LF and MI by the Incentive and Cooperative Research Programme ‘Breast cancer: cell Invasion and Motility’ of Institut Curie. Funding for this work was provided by grants from ARC (SL220100601356 and SLR20130607099), Ligue Nationale contre le Cancer (Comité de Paris), Agence Nationale pour la Recherche (ANR-08-BLAN-0111) and Institut National du Cancer (2012-1-PL BIO-02-IC-1) to PC and by core funding from Institut Curie and Centre National pour la Recherche Scientifique (CNRS).

Author Contributions

CL designed and performed the experiments, analyzed results and wrote the manuscript. EI, LF, AG, MI, EL and SV performed experiments, JC analyzed clinical samples, HBK and FR analyzed public TNBC transcriptome data set, MG supervised animal experiments, IB and AV-S selected and classified patients and analyzed clinical sample data, PC supervised the project, designed experiments and wrote the manuscript.

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Authors and Affiliations

  1. Membrane and Cytoskeleton Dynamics Group, Cell Dynamics and Compartmentalization Unit, Institut Curie, Centre National de la Recherche Scientifique UMR144, Paris, France

    C Lodillinsky, E Infante, A Guichard, L Fuhrmann, J Cyrta, M Irondelle, E Lagoutte & P Chavrier

  2. Mammalian Developmental Epigenetics Group, Genetics and Developmental Biology Unit, Institut Curie, Paris, France

    R Chaligné & A Vincent-Salomon

  3. Department of Genetics, Institut Curie, Paris, France

    S Vacher & I Bièche

  4. Translational Research Department, RT2Lab Team, Institut Curie, Paris, France

    H Bonsang-Kitzis & F Reyal

  5. Molecular Mechanisms of Mammary Gland Development Group, Cell Dynamics and Compartmentalization Unit, Institut Curie, Centre National de la Recherche Scientifique UMR144, Paris, France

    M Glukhova

  6. Pathology Department, Institut Curie, Paris, France

    A Vincent-Salomon

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  1. C Lodillinsky
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  2. E Infante
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Correspondence to C Lodillinsky or P Chavrier.

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Lodillinsky, C., Infante, E., Guichard, A. et al. p63/MT1-MMP axis is required for in situ to invasive transition in basal-like breast cancer. Oncogene 35, 344–357 (2016). https://doi.org/10.1038/onc.2015.87

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