Mutations in Apc and p53 synergize to promote mammary neoplasia

Meniel, Valerie, Hay, Trevor, Douglas-Jones, Anthony Gordon, Sansom, Owen J. ORCID: https://orcid.org/0000-0001-9540-3010 and Clarke, Alan R. ORCID: https://orcid.org/0000-0002-4281-426X 2005. Mutations in Apc and p53 synergize to promote mammary neoplasia. Cancer Research 65 (24) , pp. 410-6.

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Abstract

Mutations of Apc and p53 have both been implicated in human and murine mammary neoplasia. To investigate potential interactions between Apc and p53, we conditionally inactivated Apc in both the presence and the absence of functional p53. Apc deficiency on its own leads to the development of metaplasia but not neoplasia. We show here that these areas of metaplasia are characterized by elevated levels of both p53 and p21. In the additional absence of p53,there is rapid progression to neoplasia, with 44.4% of lymphoma-free mice developing a mammary tumor with earliest observed onset at pregnancy. To investigate the mechanism by which p53 deficiency accelerates neoplasia, we used the Rosa26R reporter strain as a marker of Cre-mediated recombination and show a role for p53 in the loss of Apc-deficient cells. This role seems limited to pregnancy and subsequent time points. We therefore show clear synergy between these two mutations in mammary gland neoplasia and present data to suggest that at least one mechanism for this acceleration is the p53-dependent loss of Apc-deficient cells.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences European Cancer Stem Cell Research Institute (ECSCRI)
Subjects:	Q Science > QH Natural history > QH426 Genetics R Medicine > R Medicine (General) R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Uncontrolled Keywords:	Apc; p53; mammary; tumorigenesis; Adenomatous Polyposis Coli Protein/biosynthesis Adenomatous Polyposis Coli Protein/deficiency Adenomatous Polyposis Coli Protein/genetics Animals Cell Cycle Proteins/biosynthesis Cell Cycle Proteins/genetics Cell Transformation, Neoplastic/genetics* Cyclin-Dependent Kinase Inhibitor p21 Cytoskeletal Proteins/biosynthesis Cytoskeletal Proteins/genetics Female Frameshift Mutation Gene Silencing Genes, APC* Genes, p53/genetics* Mammary Glands, Animal/pathology Mammary Neoplasms, Experimental/genetics* Mammary Neoplasms, Experimental/metabolism Mammary Neoplasms, Experimental/pathology Metaplasia/genetics Mice Mice, Inbred C3H Mice, Inbred C57BL Pregnancy Trans-Activators/biosynthesis Trans-Activators/genetics Tumor Suppressor Protein p53/biosynthesis Tumor Suppressor Protein p53/deficiency Tumor Suppressor Protein p53/genetics Up-Regulation beta Catenin
ISSN:	1538-7445
Last Modified:	17 Oct 2022 08:27
URI:	https://orca.cardiff.ac.uk/id/eprint/186

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