Mice heterozygous for the Apc1572T truncated allele have constitutive activation of the Wnt/β-catenin signal transduction pathway at an intermediate-level. Apc1572T mice are a model of highly-penetrant metaplastic mammary adenocarcinoma - a subtype of triple-negative breast cancer (TNBC) - in both females and males.
Riccardo Fodde, Erasmus Medical Center
Apc encodes the adenomatosis polyposis coli protein with diverse cellular functions including cellular proliferation, differentiation, cytoskeleton regulation, migration and apoptosis. APC mutations are commonly associated with intestinal tumorigenesis, and increasingly implicated with phenotypes outside of the intestine.
The hypomorphic mutation Apc1572T is designed to have stable expression of a truncated protein (Apc1572) that results in constitutive activation of the Wnt/β-catenin signal transduction pathway. The phenotype of Apc1572T mice on a C57BL/6 genetic background are described below.
All homozygous mice (Apc1572T/1572T) are embryonic lethal. Heterozygous mice (Apc1572T/+) are a model of Wnt-driven, metaplastic mammary adenocarcinoma; a subtype of triple-negative breast cancer (TNBC). Apc1572T/+ exhibit intermediate levels of Wnt/β-catenin signaling activation, resulting in highly-penetrant, multifocal mammary adenocarcinomas (virgin females [100%] and males [30%]), with subsequent pulmonary metastases in both female and male mice. Notably, the histology of the primary mammary tumors in Apc1572T/+ animals is highly heterogeneous with luminal, myoepithelial and squamous lineages, reminiscent of metaplastic carcinoma of the breast, a rare TNBC subtype characterized by an admixture of adenocarcinoma with areas of squamous, spindle cell and/or mesenchymal phenotype. Heterozygous females develop breast tumors beginning ~8 weeks of age. Some of the heterozygous males may also develop breast tumors. No increased susceptibility to spontaneous intestinal adenomas are reported for heterozygotes.
These Apc1572T mice may also be useful for isolating a subpopulation of mammary cancer stem cells (MaCSCs) that are capable of self-renewal and differentiation both in vivo and in vitro.
The donating investigator reports they observe no significant incidence of liver tumors in Apc1572T/+ (July 2016).
A targeting vector was designed by Dr. Riccardo Fodde (Erasmus Medical Center) to insert a hygromycin cassette at codon 1572 of the adenomatosis polyposis coli locus (Apc) on chromosome 18. The construct was electroporated into 129P2/OlaHsd-derived E14 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts, and chimeric males were bred with C57BL/6J females for germline transmission and to establish the colony. The Apc1572T colony was backcrossed to C57BL/6J inbred mice for at least 30 generations prior to sending black male mice to The Jackson Laboratory Repository in 2016. Upon arrival, sperm was cryopreserved. To establish our live colony, an aliquot of frozen sperm was used to fertilize C57BL/6J oocytes (Stock No. 000664).
Of note, the donating investigator reports that, at least once during backcrossing, a heterozygous female was bred to a C57BL/6J inbred male (thus the Y chromosome of the congenic strain is of C57BL/6J origin).
|Allele Name||targeted mutation 2, Riccardo Fodde|
|Allele Type||Targeted (Hypomorph)|
|Gene Symbol and Name||Apc, adenomatosis polyposis coli|
|Strain of Origin||129P2/OlaHsd|
|Molecular Note||A hygro resistance cassette was inserted at a site corresponding to codon 1572. This mutation is predicted to result in a truncated protein.|
All homozygous mice are embryonic lethal. Heterozygous females develop breast tumors beginning ~8 weeks of age. Some of the heterozygous males may also develop breast tumors. When maintaining a live colony, wildtype female mice from the colony or C57BL/6J inbred females (Stock No. 000664) may be bred to heterozygous males.
When using the Apc1572T mouse strain in a publication, please cite the originating article(s) and include JAX stock #029274 in your Materials and Methods section.