title: Constitutive HER2 signaling promotes breast cancer metastasis through cellular senescence.
abstract: Senescence, a terminal cell proliferation arrest, can be triggered by oncogenes. Oncogene-induced senescence is classically considered a tumor defense barrier. However, several findings show that, under certain circumstances, senescent cells may favor tumor progression because of their secretory phenotype. Here, we show that the expression in different breast epithelial cell lines of p95HER2, a constitutively active fragment of the tyrosine kinase receptor HER2, results in either increased proliferation or senescence. In senescent cells, p95HER2 elicits a secretome enriched in proteases, cytokines, and growth factors. This secretory phenotype is not a mere consequence of the senescence status and requires continuous HER2 signaling to be maintained. Underscoring the functional relevance of the p95HER2-induced senescence secretome, we show that p95HER2-induced senescent cells promote metastasis in vivo in a non-cell-autonomous manner.
authors.affiliation: Preclinical Research, Vall d'Hebron Institute of Oncology (VHIO, Barcelona, Spain.
authors.forename: Pier Davide
authors.initials: PD
authors.lastname: Angelini
authors.forename: Mariano F
authors.initials: MF
authors.lastname: Zacarias Fluck
authors.forename: Kim
authors.initials: K
authors.lastname: Pedersen
authors.forename: Josep Lluís
authors.initials: JL
authors.lastname: Parra-Palau
authors.forename: Marc
authors.initials: M
authors.lastname: Guiu
authors.forename: Cristina
authors.initials: C
authors.lastname: Bernadó Morales
authors.forename: Rocio
authors.initials: R
authors.lastname: Vicario
authors.forename: Antonio
authors.initials: A
authors.lastname: Luque-García
authors.forename: Nerea Peiró
authors.initials: NP
authors.lastname: Navalpotro
authors.forename: Jordi
authors.initials: J
authors.lastname: Giralt
authors.forename: Francesc
authors.initials: F
authors.lastname: Canals
authors.forename: Roger R
authors.initials: RR
authors.lastname: Gomis
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.forename: Josep
authors.initials: J
authors.lastname: Villanueva
authors.forename: Joaquín
authors.initials: J
authors.lastname: Arribas
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014183:Transplantation, Heterologous
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human