S100a4 upregulation in Pik3caH1047R;Trp53R270H;MMTV-Cre-driven mammary tumors promotes metastasis.
Animals
Cell Line, Tumor
Cell Transformation, Neoplastic
Cell Transformation, Viral
Class I Phosphatidylinositol 3-Kinases
/ genetics
Disease Models, Animal
Female
Gene Targeting
Humans
Mammary Neoplasms, Experimental
/ etiology
Mammary Tumor Virus, Mouse
Mice
Mutation
S100 Calcium-Binding Protein A4
/ metabolism
Tumor Suppressor Protein p53
/ genetics
Tumor Virus Infections
/ complications
Xenograft Model Antitumor Assays
Breast cancer
Mammary tumors
Metastasis
Pik3caH1047R
S100a4
Trp53R270H
Journal
Breast cancer research : BCR
ISSN: 1465-542X
Titre abrégé: Breast Cancer Res
Pays: England
ID NLM: 100927353
Informations de publication
Date de publication:
27 12 2019
27 12 2019
Historique:
received:
14
02
2019
accepted:
06
12
2019
entrez:
29
12
2019
pubmed:
29
12
2019
medline:
19
5
2020
Statut:
epublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 31881983
doi: 10.1186/s13058-019-1238-5
pii: 10.1186/s13058-019-1238-5
pmc: PMC6935129
doi:
Substances chimiques
S100 Calcium-Binding Protein A4
0
TP53 protein, human
0
Tumor Suppressor Protein p53
0
S100A4 protein, human
142662-27-9
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
PIK3CA protein, human
EC 2.7.1.137
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
152Références
Oncogene. 2013 Jan 17;32(3):318-26
pubmed: 22370636
Nat Rev Cancer. 2015 Feb;15(2):96-109
pubmed: 25614008
PLoS One. 2012;7(5):e36924
pubmed: 22666336
Mol Oncol. 2013 Apr;7(2):283-96
pubmed: 23474222
Genes Dev. 1989 Jul;3(7):1086-93
pubmed: 2550322
Semin Cancer Biol. 2012 Jun;22(3):216-25
pubmed: 22381352
Oncogene. 2012 Apr 26;31(17):2164-74
pubmed: 21996751
Oncotarget. 2017 May 19;8(42):73219-73239
pubmed: 29069865
R J. 2016 Aug;8(1):289-317
pubmed: 27818791
Nature. 2012 Oct 4;490(7418):61-70
pubmed: 23000897
Nucleic Acids Res. 2015 Apr 20;43(7):e47
pubmed: 25605792
Biochem Biophys Res Commun. 2010 Apr 9;394(3):443-7
pubmed: 20230796
Nature. 2015 Sep 3;525(7567):114-8
pubmed: 26266975
Cancer Res. 2017 May 1;77(9):2464-2475
pubmed: 28235761
Science. 2004 Apr 23;304(5670):554
pubmed: 15016963
Breast Cancer Res. 2016 Jan 19;18(1):9
pubmed: 26781438
FEBS Lett. 2015 Jun 22;589(14):1577-87
pubmed: 25979173
Cell Death Dis. 2018 Feb 15;9(3):261
pubmed: 29449584
Mol Med Rep. 2018 May;17(5):6405-6412
pubmed: 29532866
Bioinformatics. 2010 Apr 1;26(7):873-81
pubmed: 20147302
Cancer Res. 2011 Apr 1;71(7):2706-17
pubmed: 21324922
Breast Cancer Res Treat. 2012 Jan;131(1):41-8
pubmed: 21331622
Cell. 2004 Dec 17;119(6):847-60
pubmed: 15607980
Cancer Res. 2009 May 15;69(10):4116-24
pubmed: 19435916
Clin Cancer Res. 2015 Apr 1;21(7):1537-42
pubmed: 25670221
Cancer Res. 2011 Jul 1;71(13):4344-51
pubmed: 21482677
Nat Med. 2011 Aug 07;17(9):1116-20
pubmed: 21822287
Nature. 2015 Sep 3;525(7567):119-23
pubmed: 26266985
FASEB J. 2008 Aug;22(8):2605-22
pubmed: 18434431