Modeling invasive breast cancer: Growth factors propel progression of HER2-positive premalignant lesions

C. R. Pradeep, A. Zeisel, W. J. Köstler, M. Lauriola, J. Jacob-Hirsch, B. Haibe-Kains, N. Amariglio, N. Ben-Chetrit, A. Emde, I. Solomonov, G. Neufeld, M. Piccart, I. Sagi, C. Sotiriou, G. Rechavi, E. Domany, C. Desmedt, Y. Yarden*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)3569-3583
Number of pages15
JournalOncogene
Volume31
Issue number31
DOIs
StatePublished - 2 Aug 2012

Funding

FundersFunder number
Arresto Biosciences
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
National Cancer InstituteR01CA072981
European Commission
Deutsche Forschungsgemeinschaft

    Keywords

    • EGF
    • HER2
    • adhesion
    • breast cancer
    • hypoxia

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