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TFAP2E-DKK4 and chemoresistance in colorectal cancer.

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posted on 22.11.2019, 17:01 by Matthias PA Ebert, Marc Tänzer, Benjamin Balluff, Elke Burgermeister, Antje Karen Kretzschmar, David J. Hughes, Reimo Tetzner, Catherine Lofton-Day, Robert Rosenberg, Anke C. Reinacher-Schick, Karsten Schulmann, Andrea Tannapfel, Ralf Hofheinz, Christoph Röcken, Gisela Keller, Rupert Langer, Katja Specht, Rainer Porschen, Jan Stöhlmacher-Williams, Tibor Schuster, Philipp Ströbel, Roland M. Schmid

BACKGROUND: Chemotherapy for advanced colorectal cancer leads to improved survival; however, predictors of response to systemic treatment are not available. Genomic and epigenetic alterations of the gene encoding transcription factor AP-2 epsilon (TFAP2E) are common in human cancers. The gene encoding dickkopf homolog 4 protein (DKK4) is a potential downstream target of TFAP2E and has been implicated in chemotherapy resistance. We aimed to further evaluate the role of TFAP2E and DKK4 as predictors of the response of colorectal cancer to chemotherapy.

METHODS: We analyzed the expression, methylation, and function of TFAP2E in colorectal-cancer cell lines in vitro and in patients with colorectal cancer. We examined an initial cohort of 74 patients, followed by four cohorts of patients (total, 220) undergoing chemotherapy or chemoradiation.

RESULTS: TFAP2E was hypermethylated in 38 of 74 patients (51%) in the initial cohort. Hypermethylation was associated with decreased expression of TFAP2E in primary and metastatic colorectal-cancer specimens and cell lines. Colorectal-cancer cell lines overexpressing DKK4 showed increased chemoresistance to fluorouracil but not irinotecan or oxaliplatin. In the four other patient cohorts, TFAP2E hypermethylation was significantly associated with nonresponse to chemotherapy (P

CONCLUSIONS: TFAP2E hypermethylation is associated with clinical nonresponsiveness to chemotherapy in colorectal cancer. Functional assays confirm that TFAP2E-dependent resistance is mediated through DKK4. In patients who have colorectal cancer with TFAP2E hypermethylation, targeting of DKK4 may be an option to overcome TFAP2E-mediated drug resistance. (Funded by Deutsche Forschungsgemeinschaft and others.).

Funding

Deutsche Krebshilfe (107885 and 108096), Deutsche Forschungsgemeinschaft (SFB 824), Else Kröner Stiftung (Nr P14/07//A104/06), and Bundesministerium für Bildung und Forschung (01EZ0802 and 0315116B).

History

Comments

From New England Journal of Medicine, Ebert MP, Tänzer M, Balluff B, Burgermeister E, Kretzschmar AK, Hughes DJ, Tetzner R, Lofton-Day C, Rosenberg R, Reinacher-Schick AC, Schulmann K, Tannapfel A, Hofheinz R, Röcken C, Keller G, Langer R, Specht K, Porschen R, Stöhlmacher-Williams J, Schuster T, Ströbel P, Schmid RM., TFAP2E-DKK4 and chemoresistance in colorectal cancer, 366(1), 44-53. Copyright © (2012) Massachusetts Medical Society. Reprinted with permission.

Published Citation

Ebert MP, Tänzer M, Balluff B, Burgermeister E, Kretzschmar AK, Hughes DJ, Tetzner R, Lofton-Day C, Rosenberg R, Reinacher-Schick AC, Schulmann K, Tannapfel A, Hofheinz R, Röcken C, Keller G, Langer R, Specht K, Porschen R, Stöhlmacher-Williams J, Schuster T, Ströbel P, Schmid RM. TFAP2E-DKK4 and chemoresistance in colorectal cancer. New England Journal of Medicine. 2012;366(1):44-53. doi: 10.1056/NEJMoa1009473.

Publication Date

05/01/2012

Publisher

Massachusetts Medical Society.

PubMed ID

22216841

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