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

Gaspar C, Franken P, Molenaar L, Breukel C, van der Valk M, Smits R, Fodde R - PLoS Genet. (2009)

Bottom Line: Moreover, somatic APC mutations play a rate-limiting and initiating role in the majority of sporadic colorectal cancers.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Josephine Nefkens Institute, Erasmus MC, Rotterdam, The Netherlands.

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.

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Phenotypic characterization of Apc+/1572T mice: mammary adenocarcinomas are composed by mixed differentiation lineages with heterogeneous patterns of β-catenin intracellular accumulation and subcellular localization.Survival curves of (A) female and (B) male Apc+/1572T mice, respectively. The black, green and red lines are representative of mice in the 129Ola, F1 B6x129Ola, and B6 respectively. Please note that in these graphs, age of death represents the moment at which, due to the presence of signs of discomfort or because the tumor size exceeded 2 cm3, mice had to be euthanized according to institutional and national regulations. (C) Macroscopic image of the appearance of the mammary adenocarcinomas characteristic of the Apc1572T model. (D) Examples of global digital microscopy scans of two mammary adenocarcinomas from Apc+/1572T mice illustrative of the multi-lineage nature of these lesions.
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pgen-1000547-g003: Phenotypic characterization of Apc+/1572T mice: mammary adenocarcinomas are composed by mixed differentiation lineages with heterogeneous patterns of β-catenin intracellular accumulation and subcellular localization.Survival curves of (A) female and (B) male Apc+/1572T mice, respectively. The black, green and red lines are representative of mice in the 129Ola, F1 B6x129Ola, and B6 respectively. Please note that in these graphs, age of death represents the moment at which, due to the presence of signs of discomfort or because the tumor size exceeded 2 cm3, mice had to be euthanized according to institutional and national regulations. (C) Macroscopic image of the appearance of the mammary adenocarcinomas characteristic of the Apc1572T model. (D) Examples of global digital microscopy scans of two mammary adenocarcinomas from Apc+/1572T mice illustrative of the multi-lineage nature of these lesions.

Mentions: Together with the absence of intestinal tumors, the most striking phenotypic feature of the Apc+/1572T mouse model is undoubtedly represented by the highly penetrant incidence of multifocal mammary tumors among virgin females (100%) and males (30%), in sharp contrast with Apc+/Min and Apc+/1638N animals (1/6 and 0/14, respectively) (Table 1, Figure 3A–3D). These tumors typically arise around 3 months of age in C57BL6/J animals, though age of onset fluctuates in the different genetic backgrounds (Table 1). Histological analysis of the Apc+/1572T mammary tumors revealed a lobular arrangement with both acinar and glandular growth patterns (Figure 4A). Varying degrees of squamous metaplasia were observed in all tumors analyzed. These structures resemble skin and hair follicle differentiation (Figure 4B), in some cases strikingly similar to that observed in trichoepithelioma originated from the hair follicle. This highly heterogeneous histology with diffuse lobular hyperplasia and different degrees of squamous metaplasia was also present in smaller lesions. Thus, trans-differentiation of mammary epithelial cells takes place at an early stage during Apc–driven tumorigenesis. Immunohistochemistry (IHC) analysis revealed that all Apc+/1572T mammary adenocarcinomas (n = 12) encompass luminal and myoepithelial cell types together with areas of squamous metaplasia (Figure 4D–4E, Figure 4G–4H, and Figure 4J–4K). Heterogeneous patterns of β-catenin subcellular localization were also observed upon IHC analysis of Apc+/1572T mammary tumors with the majority of parenchymal cells showing membrane-bound and cytoplasmatic staining along with smaller patches characterized by strong nuclear staining (Figure 4M–4N).


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

Gaspar C, Franken P, Molenaar L, Breukel C, van der Valk M, Smits R, Fodde R - PLoS Genet. (2009)

Phenotypic characterization of Apc+/1572T mice: mammary adenocarcinomas are composed by mixed differentiation lineages with heterogeneous patterns of β-catenin intracellular accumulation and subcellular localization.Survival curves of (A) female and (B) male Apc+/1572T mice, respectively. The black, green and red lines are representative of mice in the 129Ola, F1 B6x129Ola, and B6 respectively. Please note that in these graphs, age of death represents the moment at which, due to the presence of signs of discomfort or because the tumor size exceeded 2 cm3, mice had to be euthanized according to institutional and national regulations. (C) Macroscopic image of the appearance of the mammary adenocarcinomas characteristic of the Apc1572T model. (D) Examples of global digital microscopy scans of two mammary adenocarcinomas from Apc+/1572T mice illustrative of the multi-lineage nature of these lesions.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2697381&req=5

pgen-1000547-g003: Phenotypic characterization of Apc+/1572T mice: mammary adenocarcinomas are composed by mixed differentiation lineages with heterogeneous patterns of β-catenin intracellular accumulation and subcellular localization.Survival curves of (A) female and (B) male Apc+/1572T mice, respectively. The black, green and red lines are representative of mice in the 129Ola, F1 B6x129Ola, and B6 respectively. Please note that in these graphs, age of death represents the moment at which, due to the presence of signs of discomfort or because the tumor size exceeded 2 cm3, mice had to be euthanized according to institutional and national regulations. (C) Macroscopic image of the appearance of the mammary adenocarcinomas characteristic of the Apc1572T model. (D) Examples of global digital microscopy scans of two mammary adenocarcinomas from Apc+/1572T mice illustrative of the multi-lineage nature of these lesions.
Mentions: Together with the absence of intestinal tumors, the most striking phenotypic feature of the Apc+/1572T mouse model is undoubtedly represented by the highly penetrant incidence of multifocal mammary tumors among virgin females (100%) and males (30%), in sharp contrast with Apc+/Min and Apc+/1638N animals (1/6 and 0/14, respectively) (Table 1, Figure 3A–3D). These tumors typically arise around 3 months of age in C57BL6/J animals, though age of onset fluctuates in the different genetic backgrounds (Table 1). Histological analysis of the Apc+/1572T mammary tumors revealed a lobular arrangement with both acinar and glandular growth patterns (Figure 4A). Varying degrees of squamous metaplasia were observed in all tumors analyzed. These structures resemble skin and hair follicle differentiation (Figure 4B), in some cases strikingly similar to that observed in trichoepithelioma originated from the hair follicle. This highly heterogeneous histology with diffuse lobular hyperplasia and different degrees of squamous metaplasia was also present in smaller lesions. Thus, trans-differentiation of mammary epithelial cells takes place at an early stage during Apc–driven tumorigenesis. Immunohistochemistry (IHC) analysis revealed that all Apc+/1572T mammary adenocarcinomas (n = 12) encompass luminal and myoepithelial cell types together with areas of squamous metaplasia (Figure 4D–4E, Figure 4G–4H, and Figure 4J–4K). Heterogeneous patterns of β-catenin subcellular localization were also observed upon IHC analysis of Apc+/1572T mammary tumors with the majority of parenchymal cells showing membrane-bound and cytoplasmatic staining along with smaller patches characterized by strong nuclear staining (Figure 4M–4N).

Bottom Line: Moreover, somatic APC mutations play a rate-limiting and initiating role in the majority of sporadic colorectal cancers.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Josephine Nefkens Institute, Erasmus MC, Rotterdam, The Netherlands.

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.

Show MeSH
Related in: MedlinePlus