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TP53  mutations are the most frequent genetic alterations in breast cancer and are associated with more aggressive disease and worse overall survival. We have created two conditional mutant  Trp53  alleles in the mouse that allow expression of  Trp53R172H  or  Trp53R245W  missense mutations in single cells surrounded by a normal stroma and immune system. Mice with  Trp53  mutations in a few breast epithelial cells develop breast cancers with high similarity to human breast cancer including triple negative. p53R245W tumors are the most aggressive and exhibit metastases to lung and liver. Development of p53R172H breast tumors with some metastases requires additional hits. Sequencing of primary tumors and metastases shows p53R245W drives a parallel evolutionary pattern of metastases. These in vivo models most closely simulate the genesis of human breast cancer and will thus be invaluable in testing novel therapeutic options.

Somatic Trp53 mutations differentially drive breast cancer and evolution of metastases