Reference SummaryGaspar C, PLoS Genet 2009 Jul;5(7):e1000547

Title

A targeted constitutive mutation in the APC tumor suppressor gene underlies mammary but not intestinal tumorigenesis.

Authors

Gaspar C; Franken P; Molenaar L; Breukel C; van der Valk M; Smits R; Fodde R

Journal

PLoS Genet

Volume

5

Issue

7

Year

2009

Pages

e1000547

Abstract

Germline mutations in the adenomatous polyposis coli (APC) gene are responsible for familial adenomatous polyposis (FAP), an autosomal dominant hereditary predisposition to the development of multiple colorectal adenomas and of a broad spectrum of extra-intestinal tumors. Moreover, somatic APC mutations play a rate-limiting and initiating role in the majority of sporadic colorectal cancers. Notwithstanding its multifunctional nature, the main tumor suppressing activity of the APC gene resides in its ability to regulate Wnt/beta-catenin signaling. Notably, genotype-phenotype correlations have been established at the APC gene between the length and stability of the truncated proteins encoded by different mutant alleles, the corresponding levels of Wnt/beta-catenin signaling activity they encode for, and the incidence and distribution of intestinal and extra-intestinal tumors. Here, we report a novel mouse model, Apc1572T, obtained by targeting a truncated mutation at codon 1572 in the endogenous Apc gene. This hypomorphic mutant allele results in intermediate levels of Wnt/beta-catenin signaling activation when compared with other Apc mutations associated with multifocal intestinal tumors. Notwithstanding the constitutive nature of the mutation, Apc(+/1572T) mice have no predisposition to intestinal cancer but develop multifocal mammary adenocarcinomas and subsequent pulmonary metastases in both genders. The histology of the Apc1572T primary mammary tumours is highly heterogeneous with luminal, myoepithelial, and squamous lineages and is reminiscent of metaplastic carcinoma of the breast in humans. The striking phenotype of Apc(+/1572T) mice suggests that specific dosages of Wnt/beta-catenin signaling activity differentially affect tissue homeostasis and initiate tumorigenesis in an organ-specific fashion.

Links

J:151494 – Mouse Genome Informatics
19578404 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
B6;129P2 Connective tissue - Fibroblast desmoid Connective tissue - Fibroblast

0

B6;129P2-ApcMin/+ Connective tissue - Fibroblast desmoid Connective tissue - Fibroblast

40 - 75

B6;129P2-Apctm1Rak/+ Connective tissue - Fibroblast desmoid Connective tissue - Fibroblast

100

B6;129P2-Apctm2Rfo/+ Connective tissue - Fibroblast desmoid Connective tissue - Fibroblast

50 - 100

[not specified]-Apctm2Rfo/+ Smad4E6sad/+ Intestine adenoma Intestine

observed

B6;129P2 Intestine tumor Intestine

0

B6;129P2-ApcMin/+ Intestine tumor Intestine

100

B6;129P2-Apctm1Rak/+ Intestine tumor Intestine

92 - 93

B6;129P2-Apctm2Rfo/+ Intestine tumor Intestine

0 - 7.7

129P2/OlaHsd Intestine tumor Intestine

0 - 60

129P2/OlaHsd-Apctm2Rfo/+ Intestine tumor Intestine

0 - 29

B6.129P2-Apctm2Rfo/+ Intestine tumor Intestine

0

[not specified]-Apctm2Rfo/+ Intestine tumor Intestine

0

[not specified]-Apctm2Rfo/+ Smad4E6sad/+ Intestine tumor Intestine

60 - 100

[not specified]-Smad4E6sad/+ Intestine tumor Intestine

0

B6;129P2 Liver tumor Liver

0

B6;129P2-ApcMin/+ Liver tumor Liver

0

B6;129P2-Apctm1Rak/+ Liver tumor Liver

0

B6;129P2-Apctm2Rfo/+ Liver tumor Liver

0 - 31

129P2/OlaHsd Liver tumor Liver

0

129P2/OlaHsd-Apctm2Rfo/+ Liver tumor Liver

11 - 29

B6.129P2-Apctm2Rfo/+ Liver tumor Liver

0 - 29

B6;129P2 Mammary gland adenocarcinoma Mammary gland

0

B6;129P2-ApcMin/+ Mammary gland adenocarcinoma Mammary gland

0 - 17

B6;129P2-Apctm1Rak/+ Mammary gland adenocarcinoma Mammary gland

0

B6;129P2-Apctm2Rfo/+ Mammary gland adenocarcinoma Mammary gland

31 - 86

129P2/OlaHsd Mammary gland adenocarcinoma Mammary gland

0

129P2/OlaHsd-Apctm2Rfo/+ Mammary gland adenocarcinoma Mammary gland

50 - 94

B6.129P2-Apctm2Rfo/+ Mammary gland adenocarcinoma Mammary gland

29 - 100

[not specified]-Apctm2Rfo/+ Mammary gland adenocarcinoma Mammary gland

0 - 100

[not specified]-Apctm2Rfo/+ Smad4E6sad/+ Mammary gland adenocarcinoma Mammary gland

0 - 100

[not specified]-Smad4E6sad/+ Mammary gland adenocarcinoma Mammary gland

0

B6.129P2-Apctm2Rfo/+ Mammary gland hyperplasia - diffuse lobular Mammary gland

observed

B6.129P2-Apctm2Rfo/+ Mammary gland metaplasia - squamous Mammary gland

observed

B6;129P2 Skin - Epidermis cyst Skin - Epidermis

0

B6;129P2-ApcMin/+ Skin - Epidermis cyst Skin - Epidermis

100

B6;129P2-Apctm1Rak/+ Skin - Epidermis cyst Skin - Epidermis

100

B6;129P2-Apctm2Rfo/+ Skin - Epidermis cyst Skin - Epidermis

50 - 64

B6;129P2 Stomach - Glandular - Pylorus tumor Stomach - Glandular - Pylorus

0

B6;129P2-ApcMin/+ Stomach - Glandular - Pylorus tumor Stomach - Glandular - Pylorus

17 - 60

B6;129P2-Apctm1Rak/+ Stomach - Glandular - Pylorus tumor Stomach - Glandular - Pylorus

100

B6;129P2-Apctm2Rfo/+ Stomach - Glandular - Pylorus tumor Stomach - Glandular - Pylorus

0 - 54

129P2/OlaHsd Stomach - Glandular - Pylorus tumor Stomach - Glandular - Pylorus

0

129P2/OlaHsd-Apctm2Rfo/+ Stomach - Glandular - Pylorus tumor Stomach - Glandular - Pylorus

0 - 7.1

B6.129P2-Apctm2Rfo/+ Stomach - Glandular - Pylorus tumor Stomach - Glandular - Pylorus

0