Early dissemination seeds metastasis in breast cancer

Hedayatollah Hosseini, Milan M.S. Obradovic, Martin Hoffmann, Kathryn L. Harper, Maria Soledad Sosa, Melanie Werner-Klein, Lahiri Kanth Nanduri, Christian Werno, Carolin Ehrl, Matthias Maneck, Nina Patwary, Gundula Haunschild, Miodrag Guzvic, Christian Reimelt, Michael Grauvogl, Norbert Eichner, Florian Weber, Andreas D. Hartkopf, Florin Andrei Taran, Sara Y. BruckerTanja Fehm, Brigitte Rack, Stefan Buchholz, Rainer Spang, Gunter Meister, Julio A. Aguirre-Ghiso, Christoph A. Klein

Research output: Contribution to journalArticlepeer-review

406 Scopus citations

Abstract

Accumulating data suggest that metastatic dissemination often occurs early during tumour formation, but the mechanisms of early metastatic spread have not yet been addressed. Here, by studying metastasis in a HER2-driven mouse breast cancer model, we show that progesterone-induced signalling triggers migration of cancer cells from early lesions shortly after HER2 activation, but promotes proliferation in advanced primary tumour cells. The switch from migration to proliferation was regulated by increased HER2 expression and tumour-cell density involving microRNA-mediated progesterone receptor downregulation, and was reversible. Cells from early, low-density lesions displayed more stemness features, migrated more and founded more metastases than cells from dense, advanced tumours. Notably, we found that at least 80% of metastases were derived from early disseminated cancer cells. Karyotypic and phenotypic analysis of human disseminated cancer cells and primary tumours corroborated the relevance of these findings for human metastatic dissemination.

Original languageEnglish (US)
Pages (from-to)552-558
Number of pages7
JournalNature
Volume540
Issue number7634
DOIs
StatePublished - Dec 22 2016
Externally publishedYes

ASJC Scopus subject areas

  • General

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