New C3H Kit N824K/WT cancer mouse model develops late-onset malignant mammary tumors with high penetrance
Abstract 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 unsati...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2022-11-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-23218-5 |
| _version_ | 1798016870617448448 |
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| author | Tanja Klein-Rodewald Kateryna Micklich Adrián Sanz-Moreno Monica Tost Julia Calzada-Wack Thure Adler Matthias Klaften Sibylle Sabrautzki Bernhard Aigner Markus Kraiger Valerie Gailus-Durner Helmut Fuchs German Mouse Clinic Consortium Albert Gründer Heike Pahl Eckhard Wolf Martin Hrabe de Angelis Birgit Rathkolb |
| author_facet | Tanja Klein-Rodewald Kateryna Micklich Adrián Sanz-Moreno Monica Tost Julia Calzada-Wack Thure Adler Matthias Klaften Sibylle Sabrautzki Bernhard Aigner Markus Kraiger Valerie Gailus-Durner Helmut Fuchs German Mouse Clinic Consortium Albert Gründer Heike Pahl Eckhard Wolf Martin Hrabe de Angelis Birgit Rathkolb |
| author_sort | Tanja Klein-Rodewald |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-11T15:57:34Z |
| format | Article |
| id | doaj.art-14dce610731c4ac3b187cabc3137d082 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-11T15:57:34Z |
| publishDate | 2022-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-14dce610731c4ac3b187cabc3137d0822022-12-22T04:15:07ZengNature PortfolioScientific Reports2045-23222022-11-0112111510.1038/s41598-022-23218-5New C3H Kit N824K/WT cancer mouse model develops late-onset malignant mammary tumors with high penetranceTanja Klein-Rodewald0Kateryna Micklich1Adrián Sanz-Moreno2Monica Tost3Julia Calzada-Wack4Thure Adler5Matthias Klaften6Sibylle Sabrautzki7Bernhard Aigner8Markus Kraiger9Valerie Gailus-Durner10Helmut Fuchs11German Mouse Clinic ConsortiumAlbert Gründer12Heike Pahl13Eckhard Wolf14Martin Hrabe de Angelis15Birgit Rathkolb16Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental HealthInstitute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental HealthInstitute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental HealthInstitute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental HealthInstitute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental HealthInstitute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental HealthInstitute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental HealthInstitute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental HealthInstitute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität MünchenInstitute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental HealthInstitute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental HealthInstitute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental HealthSection of Molecular Hematology, Department of Hematology/Oncology, Universitäts Klinikum FreiburgSection of Molecular Hematology, Department of Hematology/Oncology, Universitäts Klinikum FreiburgInstitute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität MünchenInstitute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental HealthInstitute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental HealthAbstract 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.https://doi.org/10.1038/s41598-022-23218-5 |
| spellingShingle | Tanja Klein-Rodewald Kateryna Micklich Adrián Sanz-Moreno Monica Tost Julia Calzada-Wack Thure Adler Matthias Klaften Sibylle Sabrautzki Bernhard Aigner Markus Kraiger Valerie Gailus-Durner Helmut Fuchs German Mouse Clinic Consortium Albert Gründer Heike Pahl Eckhard Wolf Martin Hrabe de Angelis Birgit Rathkolb New C3H Kit N824K/WT cancer mouse model develops late-onset malignant mammary tumors with high penetrance Scientific Reports |
| 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 |
| url | https://doi.org/10.1038/s41598-022-23218-5 |
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