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.

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We thank T. Perry for his critical reading of the manuscript. This work was supported by grants from the DFG (Kl 1233/2-1, KL 1233/3-1, KL 1233/10-1 (C.A.K.); Me2064/4-1, (G.M.); SP 938/2-1 (R.S.); INST 89/341-1 FUGG (TissueFAX)); the Dr Josef Steiner Foundation and ERC (322602) to C.A.K.; the SWCRF, CA109182, CA196521, CA163131, BC132674 (J.A.A.-G.) F31 CA183185 (K.L.H.) BC112380 (M.S.S.), NIH 1S10RR024745 Microscopy CoRE at ISMMS and by a donation from A. Jungmayer.

Author information

Author notes

    • Milan M. S. Obradović
    • , Maria Soledad Sosa
    •  & Lahiri Kanth Nanduri

    Present addresses: Tumor Heterogeneity, Metastasis and Resistance, Department of Biomedicine, University of Basel, University Hospital Basel, CH-4031 Basel, Switzerland (M.M.S.O.); Department of Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York 10029, USA (M.S.S.); Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany (L.K.N.).


  1. Experimental Medicine and Therapy Research, University of Regensburg, 93053 Regensburg, Germany

    • Hedayatollah Hosseini
    • , Milan M. S. Obradović
    • , Lahiri Kanth Nanduri
    • , Carolin Ehrl
    • , Matthias Maneck
    • , Nina Patwary
    • , Gundula Haunschild
    • , Miodrag Gužvić
    • , Christian Reimelt
    •  & Christoph A. Klein
  2. Project group ‘Personalized Tumour Therapy’, Fraunhofer Institute for Toxicology und Experimental Medicine, 93053 Regensburg, Germany

    • Martin Hoffmann
    • , Christian Werno
    •  & Christoph A. Klein
  3. Division of Hematology and Oncology, Department of Medicine, Department of Otolaryngology, Department of Oncological Sciences, Tisch Cancer Institute, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York 10029, USA

    • Kathryn L. Harper
    • , Maria Soledad Sosa
    •  & Julio A. Aguirre-Ghiso
  4. Institute of Immunology, University of Regensburg, 93053 Regensburg, Germany

    • Melanie Werner-Klein
  5. Department of Statistical Bioinformatics, Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany

    • Michael Grauvogl
    •  & Rainer Spang
  6. Biochemistry Center Regensburg (BZR), Laboratory for RNA Biology, University of Regensburg, 93053 Regensburg, Germany

    • Norbert Eichner
    •  & Gunter Meister
  7. Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany

    • Florian Weber
  8. Department of Gynecology and Obstetrics, University of Tübingen, 72076 Tübingen, Germany

    • Andreas D. Hartkopf
    • , Florin-Andrei Taran
    •  & Sara Y. Brucker
  9. Department of Gynecology and Obstetrics, University of Düsseldorf, 40225 Düsseldorf, Germany

    • Tanja Fehm
  10. Department of Gynecology and Obstetrics, University Munich, 80337 Munich, Germany

    • Brigitte Rack
  11. Department of Gynecology and Obstetrics, University Medical Center Regensburg, 93053 Regensburg, Germany

    • Stefan Buchholz


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C.A.K. and H.H. designed and evaluated core experiments. H.H. performed core experiments. M.M.S.O., C.W., L.K.N., C.E., C.R. and M.Gu. helped with in vivo, in vitro and primary culture experiments. M.H., M.M., M.Gr., R.S. and H.H. performed bioinformatic and statistical analyses. M.W.-K., K.L.H., M.S.S. and F.W. performed staining and pathological analysis. N.E. and G.M. performed miRNA sequencing and analysis. G.H., N.P., A.K.H., F.-A.T., S.Y.B., B.R., S.B. and T.F. performed DCC analysis or collected patient data. C.A.K. and H.H. wrote the manuscript with input from J.A.A.-G.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Christoph A. Klein.

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