title: Early dissemination seeds metastasis in breast cancer.
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.
authors.affiliation: Experimental Medicine and Therapy Research, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Hedayatollah
authors.initials: H
authors.lastname: Hosseini
authors.affiliation: Experimental Medicine and Therapy Research, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Milan M S
authors.initials: MMS
authors.lastname: Obradović
authors.affiliation: Project group 'Personalized Tumour Therapy', Fraunhofer Institute for Toxicology und Experimental Medicine, 93053 Regensburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hoffmann
authors.affiliation: 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.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Harper
authors.affiliation: 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.
authors.forename: Maria Soledad
authors.initials: MS
authors.lastname: Sosa
authors.affiliation: Institute of Immunology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Werner-Klein
authors.affiliation: Experimental Medicine and Therapy Research, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Lahiri Kanth
authors.initials: LK
authors.lastname: Nanduri
authors.affiliation: Project group 'Personalized Tumour Therapy', Fraunhofer Institute for Toxicology und Experimental Medicine, 93053 Regensburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Werno
authors.affiliation: Experimental Medicine and Therapy Research, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Ehrl
authors.affiliation: Experimental Medicine and Therapy Research, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Maneck
authors.affiliation: Experimental Medicine and Therapy Research, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Patwary
authors.affiliation: Experimental Medicine and Therapy Research, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Gundula
authors.initials: G
authors.lastname: Haunschild
authors.affiliation: Experimental Medicine and Therapy Research, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Miodrag
authors.initials: M
authors.lastname: Gužvić
authors.affiliation: Experimental Medicine and Therapy Research, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Reimelt
authors.affiliation: Department of Statistical Bioinformatics, Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Grauvogl
authors.affiliation: Biochemistry Center Regensburg (BZR), Laboratory for RNA Biology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Eichner
authors.affiliation: Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Weber
authors.affiliation: Department of Gynecology and Obstetrics, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Andreas D
authors.initials: AD
authors.lastname: Hartkopf
authors.affiliation: Department of Gynecology and Obstetrics, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Florin-Andrei
authors.initials: FA
authors.lastname: Taran
authors.affiliation: Department of Gynecology and Obstetrics, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Sara Y
authors.initials: SY
authors.lastname: Brucker
authors.affiliation: Department of Gynecology and Obstetrics, University of Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Fehm
authors.affiliation: Department of Gynecology and Obstetrics, University Munich, 80337 Munich, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Rack
authors.affiliation: Department of Gynecology and Obstetrics, University Medical Center Regensburg, 93053 Regensburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Buchholz
authors.affiliation: Department of Statistical Bioinformatics, Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Spang
authors.affiliation: Biochemistry Center Regensburg (BZR), Laboratory for RNA Biology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Gunter
authors.initials: G
authors.lastname: Meister
authors.affiliation: 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.
authors.forename: Julio A
authors.initials: JA
authors.lastname: Aguirre-Ghiso
authors.affiliation: Experimental Medicine and Therapy Research, University of Regensburg, 93053 Regensburg, Germany.|Project group 'Personalized Tumour Therapy', Fraunhofer Institute for Toxicology und Experimental Medicine, 93053 Regensburg, Germany.
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Klein