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

Autor: Siddiqui A; Junior Research Group 1, IZKF, FAU Erlangen-Nürnberg, Erlangen, Germany., Gollavilli PN; Junior Research Group 1, IZKF, FAU Erlangen-Nürnberg, Erlangen, Germany.; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Schwab A; Junior Research Group 1, IZKF, FAU Erlangen-Nürnberg, Erlangen, Germany., Vazakidou ME; Junior Research Group 1, IZKF, FAU Erlangen-Nürnberg, Erlangen, Germany., Ersan PG; Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey., Ramakrishnan M; Georg-Speyer-Haus Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany., Pluim D; Netherland Cancer Institute, Amsterdam, The Netherlands., Coggins S; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA., Saatci O; Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC, USA., Annaratone L; Department of Medical Sciences, University of Turin, Turin, Italy., Hm Schellens J; Netherland Cancer Institute, Amsterdam, The Netherlands., Kim B; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.; Department of Pharmacy, Kyung Hee University, Seoul, South Korea., Asangani IA; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Rasheed SAK; Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore., Marchiò C; Department of Medical Sciences, University of Turin, Turin, Italy.; Pathology Unit, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy.; Pathology Unit, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy., Sahin O; Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey.; Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC, USA., Ceppi P; Junior Research Group 1, IZKF, FAU Erlangen-Nürnberg, Erlangen, Germany. paolo.ceppi@uk-erlangen.de.
Jazyk: angličtina
Zdroj: Cell death and differentiation [Cell Death Differ] 2019 Nov; Vol. 26 (11), pp. 2223-2236. Date of Electronic Publication: 2019 Feb 08.
DOI: 10.1038/s41418-019-0289-6
Abstrakt: Cancer 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.
Databáze: MEDLINE
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