Stromal p53 Regulates Breast Cancer Development, the Immune Landscape, and Survival in an Oncogene-Specific Manner.

Autor:	Wu J; Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.; Department of Radiation Oncology and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio., Liu X; Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio., Reeser JAW; Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio., Trimboli AJ; Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio., Pécot T; Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.; Biosit - UMS CNRS 3480, Inserm 018, University of Rennes 1, Rennes, France., Sizemore GM; Department of Radiation Oncology and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio., Naidu SK; Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio., Fernandez SA; Department of Biomedical Informatics and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio., Yu L; Department of Biomedical Informatics and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio., Hallett M; Department of Biology, Concordia University, Montréal, Quebec, Canada.; Department of Biochemistry and Rosalind and Morris Goodman Cancer Centre, McGill University, Montréal, Quebec, Canada., Park M; Department of Biochemistry and Rosalind and Morris Goodman Cancer Centre, McGill University, Montréal, Quebec, Canada., Leone GW; Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.; Department of Biochemistry and Cancer Center, Medical College of Wisconsin, Wauwatosa, Wisconsin., Hildreth BE; Department of Pathology and O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama., Ostrowski MC; Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.; Department of Biochemistry and Molecular Biology and Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
Jazyk:	angličtina
Zdroj:	Molecular cancer research : MCR [Mol Cancer Res] 2022 Aug 05; Vol. 20 (8), pp. 1233-1246.
DOI:	10.1158/1541-7786.MCR-21-0960
Abstrakt:	Coevolution of tumor cells and adjacent stromal elements is a key feature during tumor progression; however, the precise regulatory mechanisms during this process remain unknown. Here, we show stromal p53 loss enhances oncogenic KrasG12D, but not ErbB2, driven tumorigenesis in murine mammary epithelia. Stroma-specific p53 deletion increases both epithelial and fibroblast proliferation in mammary glands bearing the KrasG12D oncogene in epithelia, while concurrently increasing DNA damage and/or DNA replication stress and decreasing apoptosis in the tumor cells proper. Normal epithelia was not affected by stromal p53 deletion. Tumors with p53-null stroma had a significant decrease in total, cytotoxic, and regulatory T cells; however, there was a significant increase in myeloid-derived suppressor cells, total macrophages, and M2-polarized tumor-associated macrophages, with no impact on angiogenesis or connective tissue deposition. Stroma-specific p53 deletion reprogrammed gene expression in both fibroblasts and adjacent epithelium, with p53 targets and chemokine receptors/chemokine signaling pathways in fibroblasts and DNA replication, DNA damage repair, and apoptosis in epithelia being the most significantly impacted biological processes. A gene cluster in p53-deficient mouse fibroblasts was negatively associated with patient survival when compared with two independent datasets. In summary, stroma-specific p53 loss promotes mammary tumorigenesis in an oncogene-specific manner, influences the tumor immune landscape, and ultimately impacts patient survival. Implications: Expression of the p53 tumor suppressor in breast cancer tumor stroma regulates tumorigenesis in an oncogene-specific manner, influences the tumor immune landscape, and ultimately impacts patient survival. (©2022 American Association for Cancer Research.)
Databáze:	MEDLINE
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