title: Senescence sensitivity of breast cancer cells is defined by positive feedback loop between CIP2A and E2F1.
abstract: Senescence induction contributes to cancer therapy responses and is crucial for p53-mediated tumor suppression. However, whether p53 inactivation actively suppresses senescence induction has been unclear. Here, we show that E2F1 overexpression, due to p53 or p21 inactivation, promotes expression of human oncoprotein CIP2A, which in turn, by inhibiting PP2A activity, increases stabilizing serine 364 phosphorylation of E2F1. Several lines of evidence show that increased activity of E2F1-CIP2A feedback renders breast cancer cells resistant to senescence induction. Importantly, mammary tumorigenesis is impaired in a CIP2A-deficient mouse model, and CIP2A-deficient tumors display markers of senescence induction. Moreover, high CIP2A expression predicts for poor prognosis in a subgroup of patients with breast cancer treated with senescence-inducing chemotherapy. Together, these results implicate the E2F1-CIP2A feedback loop as a key determinant of breast cancer cell sensitivity to senescence induction. This feedback loop also constitutes a promising prosenescence target for therapy of cancers with an inactivated p53-p21 pathway.
  
  
  CONCLUSIONS
  It has been recently realized that most currently used chemotherapies exert their therapeutic effect at least partly by induction of terminal cell arrest, senescence. However, the mechanisms by which cell-intrinsic senescence sensitivity is determined are poorly understood. Results of this study identify the E2F1-CIP2A positive feedback loop as a key determinant of breast cancer cell sensitivity to senescence and growth arrest induction. Our data also indicate that this newly characterized interplay between 2 frequently overexpressed oncoproteins constitutes a promising prosenescence target for therapy of cancers with inactivated p53 and p21. Finally, these results may also facilitate novel stratification strategies for selection of patients to receive senescence-inducing cancer therapies.
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
authors.forename: Anni
authors.initials: A
authors.lastname: Laine
authors.forename: Harri
authors.initials: H
authors.lastname: Sihto
authors.forename: Christophe
authors.initials: C
authors.lastname: Come
authors.forename: Mathias T
authors.initials: MT
authors.lastname: Rosenfeldt
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Zwolinska
authors.forename: Minna
authors.initials: M
authors.lastname: Niemelä
authors.forename: Anchit
authors.initials: A
authors.lastname: Khanna
authors.forename: Edward K
authors.initials: EK
authors.lastname: Chan
authors.forename: Veli-Matti
authors.initials: VM
authors.lastname: Kähäri
authors.forename: Pirkko-Liisa
authors.initials: PL
authors.lastname: Kellokumpu-Lehtinen
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.forename: Gerard I
authors.initials: GI
authors.lastname: Evan
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Junttila
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Ryan
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Marine
authors.forename: Heikki
authors.initials: H
authors.lastname: Joensuu
authors.forename: Jukka
authors.initials: J
authors.lastname: Westermarck
mesh_terms: D000818:Animals; D000969:Antinematodal Agents / Q000494:pharmacology; D001324:Autoantigens / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D050687:E2F1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D025461:Feedback, Physiological; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D061986:MCF-7 Cells; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043823:Taxoids / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014747:Vinblastine / Q000031:analogs & derivatives / Q000494:pharmacology; D000077235:Vinorelbine
chemical_list: D000969:Antinematodal Agents; D001324:Autoantigens; C500266:CIP2A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D043823:Taxoids; D016159:Tumor Suppressor Protein p53; D000077143:Docetaxel; D014747:Vinblastine; D000077235:Vinorelbine