title: The acetyltransferase Tip60 contributes to mammary tumorigenesis by modulating DNA repair.
abstract: The acetyltransferase Tip60/Kat5 acetylates both histone and non-histone proteins, and is involved in a variety of biological processes. By acetylating p53, Tip60 controls p53-dependent transcriptional activity and so is implicated as a tumor suppressor. However, many breast cancers with low Tip60 also show p53 mutation, implying that Tip60 has a tumor suppressor function independent of its acetylation of p53. Here, we show in a p53-null mouse model of sporadic invasive breast adenocarcinoma that heterozygosity for Tip60 deletion promotes mammary tumorigenesis. Low Tip60 reduces DNA repair in normal and tumor mammary epithelial cells, both under resting conditions and following genotoxic stress. We demonstrate that Tip60 controls homologous recombination (HR)-directed DNA repair, and that Tip60 levels correlate inversely with a gene expression signature associated with defective HR-directed DNA repair. In human breast cancer data sets, Tip60 mRNA is downregulated, with low Tip60 levels correlating with p53 mutations in basal-like breast cancers. Our findings indicate that Tip60 is a novel breast tumor suppressor gene whose loss results in genomic instability leading to cancer formation.
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada.|Department of Medical Biophysics, University of Toronto, University Health Network, Toronto, ON, Canada.|Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Bassi
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada.|Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Y-T
authors.initials: YT
authors.lastname: Li
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Khu
authors.affiliation: ProCURE, Catalan Institute of Oncology, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Mateo
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada.|Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: P S
authors.initials: PS
authors.lastname: Baniasadi
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada.|Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Elia
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Therapeutics Group, Toronto, ON, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Mason
authors.affiliation: Department of Medical Biophysics, University of Toronto, University Health Network, Toronto, ON, Canada.|Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: V
authors.initials: V
authors.lastname: Stambolic
authors.affiliation: Program Against Cancer Therapeutic Resistance, Breast Cancer and Systems Biology, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research, L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
authors.forename: M A
authors.initials: MA
authors.lastname: Pujana
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada.|Department of Medical Biophysics, University of Toronto, University Health Network, Toronto, ON, Canada.|Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: T W
authors.initials: TW
authors.lastname: Mak
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada.|Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Gorrini
mesh_terms: D000107:Acetylation; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D006657:Histones / Q000378:metabolism; D059765:Homologous Recombination / Q000502:physiology; D006801:Humans; D000074443:Lysine Acetyltransferase 5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008321:Mammary Glands, Animal / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D034622:RNA Interference; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D019313:BRCA1 Protein; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006657:Histones; C488588:PUMA protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000074443:Lysine Acetyltransferase 5; D051135:Rad51 Recombinase; D002945:Cisplatin