Abstract
The HER2/neu oncogene encodes a receptor-like tyrosine kinase whose overexpression in breast cancer predicts poor prognosis and resistance to conventional therapies. However, the mechanisms underlying aggressiveness of HER2 (human epidermal growth factor receptor 2)-overexpressing tumors remain incompletely understood. Because it assists epidermal growth factor (EGF) and neuregulin receptors, we overexpressed HER2 in MCF10A mammary cells and applied growth factors. HER2-overexpressing cells grown in extracellular matrix formed filled spheroids, which protruded outgrowths upon growth factor stimulation. Our transcriptome analyses imply a two-hit model for invasive growth: HER2-induced proliferation and evasion from anoikis generate filled structures, which are morphologically and transcriptionally analogous to preinvasive patients’ lesions. In the second hit, EGF escalates signaling and transcriptional responses leading to invasive growth. Consistent with clinical relevance, a gene expression signature based on the HER2/EGF-activated transcriptional program can predict poorer prognosis of a subgroup of HER2-overexpressing patients. In conclusion, the integration of a three-dimensional cellular model and clinical data attributes progression of HER2-overexpressing lesions to EGF-like growth factors acting in the context of the tumor's microenvironment.
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Change history
28 February 2024
A Correction to this paper has been published: https://doi.org/10.1038/s41388-024-02990-w
04 April 2025
The original online version of this article was revised: Following the publication of this article, the authors noted that one of the images shown in Supplementary Figure S5 (triplicate photos of SKBR3 cells treated with various inhibitory agents for 12 days) was inadvertently duplicated. The authors have corrected this unintentional error and present below the correct form of Figure S5. This image correction changed neither image quantification nor the conclusion that transcriptional induction of specific ligands and integrins is essential for EGF-induced invasive growth of HER2-overexpressing mammary cells.
11 April 2025
A Correction to this paper has been published: https://doi.org/10.1038/s41388-025-03362-8
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Acknowledgements
We thank Drs Carlos Arteaga and Ittai Ben-Porath for reagents and helpful insights. Our laboratories are supported by research grants from the National Cancer Institute (Grant CA72981), the M.D. Moross Institute for Cancer Research, Kekst Family Institute for Medical Genetics, Women's Health Research Center funded by Bennett-Pritzker Endowment Fund, Marvelle Koffler Program for Breast Cancer Research, Harry and Jeanette Weinberg Women's Health Research Endowment, Oprah Winfrey Biomedical Research Fund, Arresto Biosciences, the European Commission, and the German Research Foundation. YY is the incumbent of the Harold and Zelda Goldenberg Professorial Chair. ED is the incumbent of the Henry J Leir Professorial Chair.
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Supplementary Information accompanies the paper on the Oncogene website
The original online version of this article was revised: Following the publication of this article, the authors noted that one of the images shown in Supplementary Figure S5 (triplicate photos of SKBR3 cells treated with various inhibitory agents for 12 days) was inadvertently duplicated. The authors have corrected this unintentional error and present below the correct form of Figure S5. This image correction changed neither image quantification nor the conclusion that transcriptional induction of specific ligands and integrins is essential for EGF-induced invasive growth of HER2-overexpressing mammary cells.
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Pradeep, CR., Zeisel, A., Köstler, W. et al. Modeling invasive breast cancer: growth factors propel progression of HER2-positive premalignant lesions. Oncogene 31, 3569–3583 (2012). https://doi.org/10.1038/onc.2011.547
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DOI: https://doi.org/10.1038/onc.2011.547
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