Abstract
BackgroundPIK3CA mutations are frequent in human breast cancer. Pik3caH1047R 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 Pik3caH1047R;MMTV-Cre mouse model and found a few malignant sarcomatoid (spindle cell) carcinomas that had acquired spontaneous dominant-negative Trp53 mutations.MethodsA Pik3caH1047R;Trp53R270H;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.ResultsWe found Pik3caH1047R and Trp53R270H 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.ConclusionsPik3caH1047R;Trp53R270H;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.
Highlights
PIK3CA mutations are frequent in human breast cancer
Given this and the cooccurrence of PIK3CA and TP53 mutations in human breast cancers, we developed a Pik3caH1047R;Trp53R270H; Mouse mammary tumor virus (MMTV)-Cre double mutant model by crossing the Pik3caH1047R;MMTV-Cre mice with Trp53R270H flox mice [12]
We found that the Pik3caH1047R;Trp53R270H; MMTV-Cre double mutant mice had a shorter latency of 36.6 weeks for tumor development compared to 62 weeks in Pik3caH1047R;MMTV-Cre mice
Summary
PIK3CA mutations are frequent in human breast cancer. Pik3caH1047R mutant expression in mouse mammary gland promotes tumorigenesis. We previously generated a conditionally activatable Pik3caH1047R;MMTV-Cre mouse model and found a few malignant sarcomatoid (spindle cell) carcinomas that had acquired spontaneous dominant-negative Trp mutations. We previously developed a conditionally activatable Pik3caH1047R;MMTV-Cre mouse model where we found expression of Pik3caH1047R from the endogenous locus. In addition to benign tumors, we found a few malignant sarcomatoid (spindle cell) carcinomas that had acquired spontaneous dominantnegative Trp mutations [7]. Given this and the cooccurrence of PIK3CA and TP53 mutations in human breast cancers, we developed a Pik3caH1047R;Trp53R270H; MMTV-Cre double mutant model by crossing the Pik3caH1047R;MMTV-Cre mice with Trp53R270H flox mice [12]. We report S100a4 to be a candidate gene involved in metastasis in this model
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