title: Effect of cellular senescence on the growth of HER2-positive breast cancers.
abstract: BACKGROUND
  Oncogene-induced senescence (OIS) is a tumor suppressor mechanism. However, senescent cells remain viable and display a distinct secretome (also known as senescence-associated secretory phenotype [SASP] or senescence messaging secretome, [SMS]) that, paradoxically, includes protumorigenic factors. OIS can be triggered by ectopic overexpression of HER2, a receptor tyrosine kinase and the driving oncogene in a subtype of human breast cancer. However, cellular senescence has not been characterized in HER2-positive tumors.
  
  
  METHODS
  Using an approach based on their inability to proliferate, we isolated naturally occurring senescent cells from a variety of tumor models including HER2-positive cells, transgenic mice (n = 3), and patient-derived xenografts (PDXs) (n = 6 mice per group from one PDX derived from one patient). Using different biochemical and cell biological techniques, we characterized the secretome of these senescent cells. All statistical tests were two-sided.
  
  
  RESULTS
  We found that senescent cells arise constantly in different models of advanced breast cancers overexpressing HER2 and constitute approximately 5% of tumor cells. In these models, IL-6 and other cytokines were expressed mainly, if not exclusively, by the naturally occurring senescent cells (95.1% and 45.0% of HCC1954 cells and cells from a HER2-positive PDX expressing a senescent marker expressed IL-6, respectively). Furthermore, inhibition of IL-6 impaired the growth of the HER2-positive PDX (mean tumor volume at day 101, control vs anti-huIL-6 treated, 332.2mm(3) [95% confidence interval {CI} = 216.6 to 449.8] vs 114.4mm(3) [95% CI = 12.79 to 216.0], P = .005).
  
  
  CONCLUSIONS
  Senescent cells can contribute to the growth of tumors by providing cytokines not expressed by proliferating cells, but required by these to thrive.
authors.affiliation: Preclinical Research (MZF, BM, RV, ALG, ME, JV, JA) and Clinical Research Programs (ITR), Vall d'Hebron Institute of Oncology, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain (JA). jarribas@vhio.net.
authors.forename: Mariano F
authors.initials: MF
authors.lastname: Zacarias-Fluck
authors.affiliation: Preclinical Research (MZF, BM, RV, ALG, ME, JV, JA) and Clinical Research Programs (ITR), Vall d'Hebron Institute of Oncology, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain (JA).
authors.forename: Beatriz
authors.initials: B
authors.lastname: Morancho
authors.affiliation: Preclinical Research (MZF, BM, RV, ALG, ME, JV, JA) and Clinical Research Programs (ITR), Vall d'Hebron Institute of Oncology, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain (JA).
authors.forename: Rocio
authors.initials: R
authors.lastname: Vicario
authors.affiliation: Preclinical Research (MZF, BM, RV, ALG, ME, JV, JA) and Clinical Research Programs (ITR), Vall d'Hebron Institute of Oncology, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain (JA).
authors.forename: Antonio
authors.initials: A
authors.lastname: Luque Garcia
authors.affiliation: Preclinical Research (MZF, BM, RV, ALG, ME, JV, JA) and Clinical Research Programs (ITR), Vall d'Hebron Institute of Oncology, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain (JA).
authors.forename: Marta
authors.initials: M
authors.lastname: Escorihuela
authors.affiliation: Preclinical Research (MZF, BM, RV, ALG, ME, JV, JA) and Clinical Research Programs (ITR), Vall d'Hebron Institute of Oncology, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain (JA).
authors.forename: Josep
authors.initials: J
authors.lastname: Villanueva
authors.affiliation: Preclinical Research (MZF, BM, RV, ALG, ME, JV, JA) and Clinical Research Programs (ITR), Vall d'Hebron Institute of Oncology, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain (JA).
authors.forename: Isabel T
authors.initials: IT
authors.lastname: Rubio
authors.affiliation: Preclinical Research (MZF, BM, RV, ALG, ME, JV, JA) and Clinical Research Programs (ITR), Vall d'Hebron Institute of Oncology, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain (JA).
authors.forename: Joaquín
authors.initials: J
authors.lastname: Arribas
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000737:chemistry* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D015850:Interleukin-6; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human