Dual recombinase action in the normal and neoplastic mammary gland epithelium.
Autor: | Rädler PD; Department of Oncology, Wayne State University School of Medicine and Tumor Biology Program, Barbara Ann Karmanos Cancer Institute, 4100 John R, mail code EL01TM, Detroit, MI, 48201, USA.; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, NE, 68198, USA., Vistisen K; Department of Oncology, Wayne State University School of Medicine and Tumor Biology Program, Barbara Ann Karmanos Cancer Institute, 4100 John R, mail code EL01TM, Detroit, MI, 48201, USA., Triplett AA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, NE, 68198, USA., Dennaoui R; Department of Oncology, Wayne State University School of Medicine and Tumor Biology Program, Barbara Ann Karmanos Cancer Institute, 4100 John R, mail code EL01TM, Detroit, MI, 48201, USA., Li Y; Department of Oncology, Wayne State University School of Medicine and Tumor Biology Program, Barbara Ann Karmanos Cancer Institute, 4100 John R, mail code EL01TM, Detroit, MI, 48201, USA., Shrestha H; Department of Oncology, Wayne State University School of Medicine and Tumor Biology Program, Barbara Ann Karmanos Cancer Institute, 4100 John R, mail code EL01TM, Detroit, MI, 48201, USA., Ferraiuolo RM; Department of Oncology, Wayne State University School of Medicine and Tumor Biology Program, Barbara Ann Karmanos Cancer Institute, 4100 John R, mail code EL01TM, Detroit, MI, 48201, USA., Thangasamy A; Department of Oncology, Wayne State University School of Medicine and Tumor Biology Program, Barbara Ann Karmanos Cancer Institute, 4100 John R, mail code EL01TM, Detroit, MI, 48201, USA., Saur D; Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany., Wagner KU; Department of Oncology, Wayne State University School of Medicine and Tumor Biology Program, Barbara Ann Karmanos Cancer Institute, 4100 John R, mail code EL01TM, Detroit, MI, 48201, USA. wagnerk@karmanos.org. |
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Jazyk: | angličtina |
Zdroj: | Scientific reports [Sci Rep] 2021 Oct 21; Vol. 11 (1), pp. 20775. Date of Electronic Publication: 2021 Oct 21. |
DOI: | 10.1038/s41598-021-00231-8 |
Abstrakt: | We developed a transgenic mouse line that expresses the codon-optimized Flp recombinase under the control of the MMTV promoter in luminal epithelial cells of the mammary gland. In this report, we demonstrate the versatile applicability of the new MMTV-Flp strain to manipulate genes in a temporally and spatially controlled manner in the normal mammary gland, in luminal-type mammary tumors that overexpress ERBB2, and in a new KRAS-associated mammary cancer model. Although the MMTV-Flp is expressed in a mosaic pattern in the luminal epithelium, the Flp-mediated activation of a mutant Kras G12D allele resulted in basal-like mammary tumors that progressively acquired mesenchymal features. Besides its applicability as a tool for gene activation and cell lineage tracing to validate the cellular origin of primary and metastatic tumor cells, we employed the MMTV-Flp transgene together with the tamoxifen-inducible Cre recombinase to demonstrate that the combinatorial action of both recombinases can be used to delete or to activate genes in established tumors. In a proof-of-principle experiment, we conditionally deleted the JAK1 tyrosine kinase in KRAS-transformed mammary cancer cells using the dual recombinase approach and found that lack of JAK1 was sufficient to block the constitutive activation of STAT3. The collective results from the various lines of investigation showed that it is, in principle, feasible to manipulate genes in a ligand-controlled manner in neoplastic mammary epithelial cells, even when cancer cells acquire a state of cellular plasticity that may no longer support the expression of the MMTV-Flp transgene. (© 2021. The Author(s).) |
Databáze: | MEDLINE |
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