S100a4 upregulation in Pik3caH1047R;Trp53R270H;MMTV-Cre-driven mammary tumors promotes metastasis
BACKGROUND: PIK3CA 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.
METHODS: A 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.
RESULTS: We 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.
CONCLUSIONS: Pik3caH1047R;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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:21 |
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| Enthalten in: |
Breast cancer research : BCR - 21(2019), 1 vom: 27. Dez., Seite 152 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yuan, Wenlin [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 18.05.2020 Date Revised 18.05.2020 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1186/s13058-019-1238-5 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM304820008 |
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| 100 | 1 | |a Yuan, Wenlin |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a S100a4 upregulation in Pik3caH1047R;Trp53R270H;MMTV-Cre-driven mammary tumors promotes metastasis |
| 264 | 1 | |c 2019 | |
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| 500 | |a Date Completed 18.05.2020 | ||
| 500 | |a Date Revised 18.05.2020 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a BACKGROUND: PIK3CA 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 | ||
| 520 | |a METHODS: A 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 | ||
| 520 | |a RESULTS: We 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 | ||
| 520 | |a CONCLUSIONS: Pik3caH1047R;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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Breast cancer | |
| 650 | 4 | |a Mammary tumors | |
| 650 | 4 | |a Metastasis | |
| 650 | 4 | |a Pik3caH1047R | |
| 650 | 4 | |a S100a4 | |
| 650 | 4 | |a Trp53R270H | |
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| 650 | 7 | |a TP53 protein, human |2 NLM | |
| 650 | 7 | |a Tumor Suppressor Protein p53 |2 NLM | |
| 650 | 7 | |a S100A4 protein, human |2 NLM | |
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| 650 | 7 | |a PIK3CA protein, human |2 NLM | |
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| 700 | 1 | |a Goldstein, Leonard D |e verfasserin |4 aut | |
| 700 | 1 | |a Durinck, Steffen |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Ying-Jiun |e verfasserin |4 aut | |
| 700 | 1 | |a Nguyen, Thong T |e verfasserin |4 aut | |
| 700 | 1 | |a Kljavin, Noelyn M |e verfasserin |4 aut | |
| 700 | 1 | |a Sokol, Ethan S |e verfasserin |4 aut | |
| 700 | 1 | |a Stawiski, Eric W |e verfasserin |4 aut | |
| 700 | 1 | |a Haley, Benjamin |e verfasserin |4 aut | |
| 700 | 1 | |a Ziai, James |e verfasserin |4 aut | |
| 700 | 1 | |a Modrusan, Zora |e verfasserin |4 aut | |
| 700 | 1 | |a Seshagiri, Somasekar |e verfasserin |4 aut | |
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