title: The DNA resection protein CtIP promotes mammary tumorigenesis.
abstract: Many DNA repair factors act to suppress tumor formation by preserving genomic stability. Similarly, the CtIP protein, which interacts with the BRCA1 tumor suppressor, is also thought to have tumor suppression activity. Through its role in DNA end resection, CtIP facilitates DNA double-strand break (DSB) repair by homologous recombination (DSBR-HR) and microhomology-mediated end joining (MMEJ). In addition, however, CtIP has also been implicated in the formation of aberrant chromosomal rearrangements in an MMEJ-dependent manner, an activity that could potentially promote tumor development by increasing genome instability. To clarify whether CtIP acts in vivo to suppress or promote tumorigenesis, we have examined its oncogenic potential in mouse models of human breast cancer. Surprisingly, mice heterozygous for a null Ctip allele did not display an increased susceptibility to tumor formation. Moreover, mammary-specific biallelic CtIP ablation did not elicit breast tumors in a manner reminiscent of BRCA1 loss. Instead, CtIP inactivation dramatically reduced the kinetics of mammary tumorigenesis in mice bearing mammary-specific lesions of the p53 gene. Thus, unlike other repair factors, CtIP is not a tumor suppressor, but has oncogenic properties that can promote tumorigenesis, consistent with its ability to facilitate MMEJ-dependent chromosomal instability. Consequently, inhibition of CtIP-mediated MMEJ may prove effective against tumor types, such as human breast cancer, that display MMEJ-dependent chromosomal rearrangements.
authors.affiliation: Institute for Cancer Genetics, Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Colleen R
authors.initials: CR
authors.lastname: Reczek
authors.affiliation: Institute for Cancer Genetics, Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.|Current address: Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University Wexner Medical Center and Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Reena
authors.initials: R
authors.lastname: Shakya
authors.affiliation: Institute for Cancer Genetics, Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Yana
authors.initials: Y
authors.lastname: Miteva
authors.affiliation: Institute for Cancer Genetics, Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Matthias
authors.initials: M
authors.lastname: Szabolcs
authors.affiliation: Institute for Cancer Genetics, Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.|Current address: Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University Wexner Medical Center and Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ludwig
authors.affiliation: Institute for Cancer Genetics, Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Baer
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004249:DNA Damage; D059766:DNA End-Joining Repair; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D006579:Heterozygote; D008321:Mammary Glands, Animal / Q000378:metabolism* / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008894:Milk Proteins / Q000235:genetics / Q000378:metabolism; D009857:Oncogenes; D010641:Phenotype; D059767:Recombinational DNA Repair; D013997:Time Factors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D008894:Milk Proteins; D016159:Tumor Suppressor Protein p53; C501070:RBBP8 protein, mouse; C024471:whey acidic proteins
keywords: CtIP; DNA break repair; DNA resection; chromosomal instability; tumor suppression