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Mutations in Apc and p53 Synergize to Promote Mammary Neoplasia

¹ School of Biological Sciences, Cardiff University and ² Department of Pathology, University of Wales College of Medicine, Cardiff, United Kingdom

Requests for reprints: Alan R. Clarke, School of Biological Sciences, Cardiff University, Cardiff CF103US, United Kingdom. Phone: 44-2920-874609; Fax: 44-2920-874116; E-mail: clarkear{at}cf.ac.uk.

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.

Key Words: Apc • p53 • mammary • tumorigenesis

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