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An Orthotopic Mouse Model of Spontaneous Breast Cancer Metastasis
Published on: August 14, 2016
Common Genomic Aberrations in Mouse and Human Breast Cancers with Concurrent P53 Deficiency and Activated
Jarrod D Martinez1, Qianxing Mo2, Yixiang Xu1
1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030.
Abstract:
Simultaneous P53 loss and activation of the PTEN-restricted PI3K-AKT pathway frequently occur in aggressive breast cancers. P53 loss causes genome instability, while PTEN loss and/or activating mutations of PIK3CA and AKT promote cancer cell proliferation that also increases incidences of genomic aberrations. However, the genomic alterations associated with P53 loss and activated PTEN-PI3K-AKT signaling in breast cancer have not been defined. Spatiotemporally controlled breast cancer models with inactivation of both P53 and Pten in adult mice have not been established for studying genomic alterations. Herein, we deleted both floxed Pten and Tp53 genes in the mammary gland epithelial cells in adult mice using a RCAS virus-mediated Cre-expressing system. These mice developed small tumors in 21 weeks, and poorly differentiated larger tumors in 26 weeks. In these tumors, we identified 360 genes mutated by nonsynonymous point mutations and small insertions and deletions (NSPMs/InDels), 435 genes altered by copy number amplifications (CNAs), and 450 genes inactivated by copy number deletions (CNDs). Importantly, 22.2%, 75.9% and 27.3% of these genes were also altered in human breast tumors with P53 and PTEN losses or P53 loss and activated PI3K-AKT signaling by NSPMs/InDels, CNAs and CNDs, respectively. Therefore, inactivation of P53 and Pten in adult mice causes rapid-growing breast tumors, and these tumors recapitulate a significant number of genetic aberrations in human breast tumors with inactivated P53 and activated PTEN-PI3K-AKT signaling. Further characterization of these commonly altered genes in breast cancer should help to identify novel cancer-driving genes and molecular targets for developing therapeutics.
Insights
Simultaneous P53 loss and PTEN-PI3K-AKT pathway activation drive aggressive breast cancers. This study developed a mouse model to identify key genomic alterations in these aggressive tumors, aiding therapeutic target discovery.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Simultaneous P53 loss and PTEN-PI3K-AKT pathway activation are common in aggressive breast cancers.
- P53 loss leads to genome instability, while PTEN/PI3K/AKT alterations promote proliferation and genomic aberrations.
- Genomic alterations associated with these specific molecular events in breast cancer remain underexplored.
Purpose of the Study:
- To establish a spatiotemporally controlled mouse model for studying genomic alterations in breast cancer with concurrent P53 and Pten inactivation.
- To define the spectrum of genomic alterations, including point mutations, copy number amplifications, and deletions, in these experimentally induced tumors.
- To compare the identified genomic alterations with those found in human breast tumors exhibiting P53 loss and/or activated PI3K-AKT signaling.
Main Methods:
- Utilized a RCAS virus-mediated Cre-expressing system to delete floxed Pten and Tp53 genes in adult mouse mammary gland epithelial cells.
- Developed and analyzed tumors arising in these genetically engineered mice.
- Characterized genomic alterations using nonsynonymous point mutations and small insertions/deletions (NSPMs/InDels), copy number amplifications (CNAs), and copy number deletions (CNDs).
Main Results:
- Inactivated P53 and Pten in adult mice rapidly induced aggressive breast tumors within 21-26 weeks.
- Identified 360 genes with NSPMs/InDels, 435 genes with CNAs, and 450 genes with CNDs in the mouse tumors.
- Found significant overlap between mouse tumor genomic alterations and human breast tumors with P53 loss and/or activated PI3K-AKT signaling (22.2% NSPMs/InDels, 75.9% CNAs, 27.3% CNDs).
Conclusions:
- Inactivation of P53 and Pten in adult mice generates a relevant model for aggressive breast cancer.
- This model recapitulates key genetic aberrations observed in human breast tumors with P53 loss and activated PI3K-AKT signaling.
- Further investigation of commonly altered genes can identify novel cancer drivers and therapeutic targets for breast cancer.
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