Thymidylate synthase maintains the de-differentiated state of triple negative breast cancers

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buir.contributor.authorErsan, Pelin G.
buir.contributor.authorŞahin, Özgür
dc.citation.epage2236en_US
dc.citation.issueNumber11
dc.citation.spage2223en_US
dc.citation.volumeNumber26en_US
dc.contributor.authorSiddiqui, A.en_US
dc.contributor.authorGollavilli, P. N.en_US
dc.contributor.authorSchwab, A.en_US
dc.contributor.authorVazakidou, M. E.en_US
dc.contributor.authorErsan, Pelin G.en_US
dc.contributor.authorRamakrishnan, M.en_US
dc.contributor.authorPluim, D.en_US
dc.contributor.authorCoggins, Si’A.en_US
dc.contributor.authorSaatçi, Ö.en_US
dc.contributor.authorAnnaratone, L.en_US
dc.contributor.authorSchellens, J. HMen_US
dc.contributor.authorKim, B.en_US
dc.contributor.authorAsangani, İ. A.en_US
dc.contributor.authorRasheed, S. A. K.en_US
dc.contributor.authorMarchiò, C.en_US
dc.contributor.authorŞahin, Özgüren_US
dc.contributor.authorCeppi, P.en_US
dc.date.accessioned2020-02-10T11:48:18Z
dc.date.available2020-02-10T11:48:18Z
dc.date.issued2019-02
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.description.abstractCancer cells frequently boost nucleotide metabolism (NM) to support their increased proliferation, but the consequences of elevated NM on tumor de-differentiation are mostly unexplored. Here, we identified a role for thymidylate synthase (TS), a NM enzyme and established drug target, in cancer cell de-differentiation and investigated its clinical significance in breast cancer (BC). In vitro, TS knockdown increased the population of CD24+ differentiated cells, and attenuated migration and sphere-formation. RNA-seq profiling indicated repression of epithelial-to-mesenchymal transition (EMT) signature genes upon TS knockdown, and TS-deficient cells showed an increased ability to invade and metastasize in vivo, consistent with the occurrence of a partial EMT phenotype. Mechanistically, TS enzymatic activity was found essential for maintenance of the EMT/stem-like state by fueling a dihydropyrimidine dehydrogenase—dependent pyrimidine catabolism. In patient tissues, TS levels were found significantly higher in poorly differentiated and in triple negative BC, and strongly correlated with worse prognosis. The present study provides the rationale to study in-depth the role of NM at the crossroads of proliferation and differentiation, and depicts new avenues for the design of novel drug combinations for the treatment of BC.en_US
dc.description.provenanceSubmitted by Evrim Ergin (eergin@bilkent.edu.tr) on 2020-02-10T11:48:18Z No. of bitstreams: 1 Thymidylate_synthase_maintains_the_de-differentiated_state_of_triple_negative_breast_cancers.pdf: 3372248 bytes, checksum: b5e28b8842fd473236664f61ebb1d71d (MD5)en
dc.description.provenanceMade available in DSpace on 2020-02-10T11:48:18Z (GMT). No. of bitstreams: 1 Thymidylate_synthase_maintains_the_de-differentiated_state_of_triple_negative_breast_cancers.pdf: 3372248 bytes, checksum: b5e28b8842fd473236664f61ebb1d71d (MD5) Previous issue date: 2019-02en
dc.identifier.doi10.1038/s41418-019-0289-6en_US
dc.identifier.eissn1476-5403
dc.identifier.urihttp://hdl.handle.net/11693/53231
dc.language.isoEnglishen_US
dc.publisherNature Publishing Groupen_US
dc.relation.isversionofhttps:// doi.org/10.1038/s41418-019-0289-6en_US
dc.source.titleCell Death and Differentiationen_US
dc.subjectCancer metabolismen_US
dc.subjectCancer stem cellsen_US
dc.titleThymidylate synthase maintains the de-differentiated state of triple negative breast cancersen_US
dc.typeArticleen_US

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