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New C3H Kit(N824K/WT) cancer mouse model develops late-onset malignant mammary tumors with high penetrance

Gastro-intestinal stromal tumors and acute myeloid leukemia induced by activating stem cell factor receptor tyrosine kinase (KIT) mutations are highly malignant. Less clear is the role of KIT mutations in the context of breast cancer. Treatment success of KIT-induced cancers is still unsatisfactory...

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Autores principales: Klein-Rodewald, Tanja, Micklich, Kateryna, Sanz-Moreno, Adrián, Tost, Monica, Calzada-Wack, Julia, Adler, Thure, Klaften, Matthias, Sabrautzki, Sibylle, Aigner, Bernhard, Kraiger, Markus, Gailus-Durner, Valerie, Fuchs, Helmut, Gründer, Albert, Pahl, Heike, Wolf, Eckhard, Hrabe de Angelis, Martin, Rathkolb, Birgit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9671887/
https://www.ncbi.nlm.nih.gov/pubmed/36396684
http://dx.doi.org/10.1038/s41598-022-23218-5
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author Klein-Rodewald, Tanja
Micklich, Kateryna
Sanz-Moreno, Adrián
Tost, Monica
Calzada-Wack, Julia
Adler, Thure
Klaften, Matthias
Sabrautzki, Sibylle
Aigner, Bernhard
Kraiger, Markus
Gailus-Durner, Valerie
Fuchs, Helmut
Gründer, Albert
Pahl, Heike
Wolf, Eckhard
Hrabe de Angelis, Martin
Rathkolb, Birgit
author_facet Klein-Rodewald, Tanja
Micklich, Kateryna
Sanz-Moreno, Adrián
Tost, Monica
Calzada-Wack, Julia
Adler, Thure
Klaften, Matthias
Sabrautzki, Sibylle
Aigner, Bernhard
Kraiger, Markus
Gailus-Durner, Valerie
Fuchs, Helmut
Gründer, Albert
Pahl, Heike
Wolf, Eckhard
Hrabe de Angelis, Martin
Rathkolb, Birgit
author_sort Klein-Rodewald, Tanja
collection PubMed
description Gastro-intestinal stromal tumors and acute myeloid leukemia induced by activating stem cell factor receptor tyrosine kinase (KIT) mutations are highly malignant. Less clear is the role of KIT mutations in the context of breast cancer. Treatment success of KIT-induced cancers is still unsatisfactory because of primary or secondary resistance to therapy. Mouse models offer essential platforms for studies on molecular disease mechanisms in basic cancer research. In the course of the Munich N-ethyl-N-nitrosourea (ENU) mutagenesis program a mouse line with inherited polycythemia was established. It carries a base-pair exchange in the Kit gene leading to an amino acid exchange at position 824 in the activation loop of KIT. This KIT variant corresponds to the N822K mutation found in human cancers, which is associated with imatinib-resistance. C3H Kit(N824K/WT) mice develop hyperplasia of interstitial cells of Cajal and retention of ingesta in the cecum. In contrast to previous Kit-mutant models, we observe a benign course of gastrointestinal pathology associated with prolonged survival. Female mutants develop mammary carcinomas at late onset and subsequent lung metastasis. The disease model complements existing oncology research platforms. It allows for addressing the role of KIT mutations in breast cancer and identifying genetic and environmental modifiers of disease progression.
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spelling pubmed-96718872022-11-19 New C3H Kit(N824K/WT) cancer mouse model develops late-onset malignant mammary tumors with high penetrance Klein-Rodewald, Tanja Micklich, Kateryna Sanz-Moreno, Adrián Tost, Monica Calzada-Wack, Julia Adler, Thure Klaften, Matthias Sabrautzki, Sibylle Aigner, Bernhard Kraiger, Markus Gailus-Durner, Valerie Fuchs, Helmut Gründer, Albert Pahl, Heike Wolf, Eckhard Hrabe de Angelis, Martin Rathkolb, Birgit Sci Rep Article Gastro-intestinal stromal tumors and acute myeloid leukemia induced by activating stem cell factor receptor tyrosine kinase (KIT) mutations are highly malignant. Less clear is the role of KIT mutations in the context of breast cancer. Treatment success of KIT-induced cancers is still unsatisfactory because of primary or secondary resistance to therapy. Mouse models offer essential platforms for studies on molecular disease mechanisms in basic cancer research. In the course of the Munich N-ethyl-N-nitrosourea (ENU) mutagenesis program a mouse line with inherited polycythemia was established. It carries a base-pair exchange in the Kit gene leading to an amino acid exchange at position 824 in the activation loop of KIT. This KIT variant corresponds to the N822K mutation found in human cancers, which is associated with imatinib-resistance. C3H Kit(N824K/WT) mice develop hyperplasia of interstitial cells of Cajal and retention of ingesta in the cecum. In contrast to previous Kit-mutant models, we observe a benign course of gastrointestinal pathology associated with prolonged survival. Female mutants develop mammary carcinomas at late onset and subsequent lung metastasis. The disease model complements existing oncology research platforms. It allows for addressing the role of KIT mutations in breast cancer and identifying genetic and environmental modifiers of disease progression. Nature Publishing Group UK 2022-11-17 /pmc/articles/PMC9671887/ /pubmed/36396684 http://dx.doi.org/10.1038/s41598-022-23218-5 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Klein-Rodewald, Tanja
Micklich, Kateryna
Sanz-Moreno, Adrián
Tost, Monica
Calzada-Wack, Julia
Adler, Thure
Klaften, Matthias
Sabrautzki, Sibylle
Aigner, Bernhard
Kraiger, Markus
Gailus-Durner, Valerie
Fuchs, Helmut
Gründer, Albert
Pahl, Heike
Wolf, Eckhard
Hrabe de Angelis, Martin
Rathkolb, Birgit
New C3H Kit(N824K/WT) cancer mouse model develops late-onset malignant mammary tumors with high penetrance
title New C3H Kit(N824K/WT) cancer mouse model develops late-onset malignant mammary tumors with high penetrance
title_full New C3H Kit(N824K/WT) cancer mouse model develops late-onset malignant mammary tumors with high penetrance
title_fullStr New C3H Kit(N824K/WT) cancer mouse model develops late-onset malignant mammary tumors with high penetrance
title_full_unstemmed New C3H Kit(N824K/WT) cancer mouse model develops late-onset malignant mammary tumors with high penetrance
title_short New C3H Kit(N824K/WT) cancer mouse model develops late-onset malignant mammary tumors with high penetrance
title_sort new c3h kit(n824k/wt) cancer mouse model develops late-onset malignant mammary tumors with high penetrance
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9671887/
https://www.ncbi.nlm.nih.gov/pubmed/36396684
http://dx.doi.org/10.1038/s41598-022-23218-5
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