Modeling ductal carcinoma in situ: A HER2-Notch3 collaboration enables luminal filling

C. R. Pradeep, W. J. Köstler, M. Lauriola, R. Z. Granit, F. Zhang, J. Jacob-Hirsch, G. Rechavi, H. B. Nair, B. T. Hennessy, A. M. Gonzalez-Angulo, R. R. Tekmal, I. Ben-Porath, G. B. Mills, E. Domany, Y. Yarden

    Research output: Contribution to journalArticle

    28 Scopus citations

    Abstract

    A large fraction of ductal carcinoma in situ (DCIS), a non-invasive precursor lesion of invasive breast cancer, overexpresses the HER2/neu oncogene. The ducts of DCIS are abnormally filled with cells that evade apoptosis, but the underlying mechanisms remain incompletely understood. We overexpressed HER2 in mammary epithelial cells and observed growth factor-independent proliferation. When grown in extracellular matrix as three-dimensional spheroids, control cells developed a hollow lumen, but HER2-overexpressing cells populated the lumen by evading apoptosis. We demonstrate that HER2 overexpression in this cellular model of DCIS drives transcriptional upregulation of multiple components of the Notch survival pathway. Importantly, luminal filling required upregulation of a signaling pathway comprising Notch3, its cleaved intracellular domain and the transcriptional regulator HES1, resulting in elevated levels of c-MYC and cyclin D1. In line with HER2-Notch3 collaboration, drugs intercepting either arm reverted the DCIS-like phenotype. In addition, we report upregulation of Notch3 in hyperplastic lesions of HER2 transgenic animals, as well as an association between HER2 levels and expression levels of components of the Notch pathway in tumor specimens of breast cancer patients. Therefore, it is conceivable that the integration of the Notch and HER2 signaling pathways contributes to the pathophysiology of DCIS.

    Original languageEnglish (US)
    Pages (from-to)907-917
    Number of pages11
    JournalOncogene
    Volume31
    Issue number7
    DOIs
    StatePublished - Feb 16 2012

    Keywords

    • DCIS
    • breast cancer
    • growth factor
    • receptor tyrosine kinase
    • signal transduction
    • spheroids

    ASJC Scopus subject areas

    • Molecular Biology
    • Genetics
    • Cancer Research

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  • Cite this

    Pradeep, C. R., Köstler, W. J., Lauriola, M., Granit, R. Z., Zhang, F., Jacob-Hirsch, J., Rechavi, G., Nair, H. B., Hennessy, B. T., Gonzalez-Angulo, A. M., Tekmal, R. R., Ben-Porath, I., Mills, G. B., Domany, E., & Yarden, Y. (2012). Modeling ductal carcinoma in situ: A HER2-Notch3 collaboration enables luminal filling. Oncogene, 31(7), 907-917. https://doi.org/10.1038/onc.2011.279