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Background   PIK3CA  mutations are frequent in human breast cancer.  Pik3ca H1047R mutant expression in mouse mammary gland promotes tumorigenesis.  TP53  mutations co-occur with  PIK3CA  mutations in human breast cancers. We previously generated a conditionally activatable  Pik3ca H1047R; MMTV-Cre  mouse model and found a few malignant sarcomatoid (spindle cell) carcinomas that had acquired spontaneous dominant-negative  Trp53  mutations.    Methods  A  Pik3ca H1047R; Trp53 R270H; MMTV-Cre  double mutant mouse breast cancer model was generated. Tumors were characterized by histology, marker analysis, transcriptional profiling, single-cell RNA-seq, and bioinformatics. Cell lines were developed from mutant tumors and used to identify and confirm genes involved in metastasis.    Results  We found  Pik3ca H1047R and  Trp53 R270H cooperate in driving oncogenesis in mammary glands leading to a shorter latency than either alone. Double mutant mice develop multiple histologically distinct mammary tumors, including adenocarcinoma and sarcomatoid (spindle cell) carcinoma. We found some tumors to be invasive and a few metastasized to the lung and/or the lymph node. Single-cell RNA-seq analysis of the tumors identified epithelial, stromal, myeloid, and T cell groups. Expression analysis of the metastatic tumors identified  S100a4  as a top candidate gene associated with metastasis. Metastatic tumors contained a much higher percentage of epithelial–mesenchymal transition (EMT)-signature positive and  S100a4 -expressing cells. CRISPR/CAS9-mediated knockout of  S100a4  in a metastatic tumor-derived cell line disrupted its metastatic potential indicating a role for  S100a4  in metastasis.    Conclusions   Pik3ca H1047R; Trp53 R270H; MMTV-Cre  mouse provides a preclinical model to mimic a subtype of human breast cancers that carry both  PIK3CA  and  TP53  mutations. It also allows for understanding the cooperation between the two mutant genes in tumorigenesis. Our model also provides a system to study metastasis and develop therapeutic strategies for  PIK3CA / TP53  double-positive cancers. S100a4 found involved in metastasis in this model can be a potential diagnostic and therapeutic target.

S100a4 upregulation in Pik3caH1047R;Trp53R270H;MMTV-Cre-driven mammary tumors promotes metastasis