Tyrosine phosphatase SHP2 promotes breast cancer progression and maintains tumor-initiating cells via activation of key transcription factors and a positive feedback signaling loop

Nicola Aceto, Nina Sausgruber, Heike Brinkhaus, Dimos Gaidatzis, Georg Martiny-Baron, Giovanni Mazzarol, Stefano Confalonieri, Micaela Quarto, Guang Hu, Piotr J. Balwierz, Mikhail Pachkov, Stephen J. Elledge, Erik Van Nimwegen, Michael B. Stadler, Mohamed Bentires-Alj

Research output: Contribution to journalArticlepeer-review

Abstract

New cancer therapies are likely to arise from an in-depth understanding of the signaling networks influencing tumor initiation, progression and metastasis. We show a fundamental role for Src-homology 2 domain-containing phosphatase 2 (SHP2) in these processes in human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancers. Knockdown of SHP2 eradicated breast tumor-initiating cells in xenograft models, and SHP2 depletion also prevented invasion in three-dimensional cultures and in a transductal invasion assay in vivo. Notably, SHP2 knockdown in established breast tumors blocked their growth and reduced metastasis. Mechanistically, SHP2 activated stemness-associated transcription factors, including v-myc myelocytomatosis viral oncogene homolog (c-Myc) and zinc finger E-box binding homeobox 1 (ZEB1), which resulted in the repression of let-7 microRNA and the expression of a set of 'SHP2 signature' genes. We found these genes to be simultaneously activated in a large subset of human primary breast tumors that are associated with invasive behavior and poor prognosis. These results provide new insights into the signaling cascades influencing tumor-initiating cells as well as a rationale for targeting SHP2 in breast cancer.

Original languageEnglish
Pages (from-to)529-537
Number of pages9
JournalNature Medicine
Volume18
Issue number4
DOIs
Publication statusPublished - Apr 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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