Functional redundancy between Apc and Apc2 regulates tissue homeostasis and prevents tumorigenesis in murine mammary epithelium

Aberrant Wnt signaling within breast cancer is associated with poor prognosis, but regulation of this pathway in breast tissue remains poorly understood and the consequences of immediate or long-term dysregulation remain elusive. The exact contribution of the Wnt-regulating proteins adenomatous poly...

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Veröffentlicht in:Oncogene 2017-03, Vol.36 (13), p.1793-1803
Hauptverfasser: Daly, C S, Shaw, P, Ordonez, L D, Williams, G T, Quist, J, Grigoriadis, A, Van Es, J H, Clevers, H, Clarke, A R, Reed, K R
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container_end_page 1803
container_issue 13
container_start_page 1793
container_title Oncogene
container_volume 36
creator Daly, C S
Shaw, P
Ordonez, L D
Williams, G T
Quist, J
Grigoriadis, A
Van Es, J H
Clevers, H
Clarke, A R
Reed, K R
description Aberrant Wnt signaling within breast cancer is associated with poor prognosis, but regulation of this pathway in breast tissue remains poorly understood and the consequences of immediate or long-term dysregulation remain elusive. The exact contribution of the Wnt-regulating proteins adenomatous polyposis coli (APC) and APC2 in the pathogenesis of human breast cancer are ill-defined, but our analysis of publically available array data sets indicates that tumors with concomitant low expression of both proteins occurs more frequently in the ‘triple negative’ phenotype, which is a subtype of breast cancer with particularly poor prognosis. We have used mouse transgenics to delete Apc and/or Apc2 from mouse mammary epithelium to elucidate the significance of these proteins in mammary homeostasis and delineate their influences on Wnt signaling and tumorigenesis. Loss of either protein alone failed to affect Wnt signaling levels or tissue homeostasis. Strikingly, concomitant loss led to local disruption of β-catenin status, disruption in epithelial integrity, cohesion and polarity, increased cell division and a distinctive form of ductal hyperplasia with ‘squamoid’ ghost cell nodules in young animals. Upon aging, the development of Wnt activated mammary carcinomas with squamous differentiation was accompanied by a significantly reduced survival. This novel Wnt-driven mammary tumor model highlights the importance of functional redundancies existing between the Apc proteins both in normal homeostasis and in tumorigenesis.
doi_str_mv 10.1038/onc.2016.342
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source MEDLINE; Nature; Alma/SFX Local Collection
subjects 38
38/1
631/208/68
631/67/1347
631/67/68
64/60
82/51
Adenomatous polyposis coli
Adenomatous Polyposis Coli Protein - genetics
Adenomatous Polyposis Coli Protein - metabolism
Analysis
Animals
Apoptosis
beta Catenin - genetics
beta Catenin - metabolism
Breast cancer
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Breast Neoplasms - mortality
Breast Neoplasms - pathology
Carcinogenesis
Carcinogenesis - genetics
Carcinogenesis - metabolism
Cell Biology
Cell division
Cell Transformation, Neoplastic - genetics
Cell Transformation, Neoplastic - metabolism
Cytoskeletal Proteins - genetics
Cytoskeletal Proteins - metabolism
DNA Copy Number Variations
Epithelium
Epithelium - metabolism
Epithelium - pathology
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Genetic disorders
Genetic regulation
Homeostasis
Homeostasis - genetics
Human Genetics
Humans
Hyperplasia
Internal Medicine
Lactation - genetics
Mammary gland
Mammary Neoplasms, Animal
Medical prognosis
Medicine
Medicine & Public Health
Mice
Mice, Transgenic
Oncology
Original
original-article
Phenotypes
Physiological aspects
Polyposis coli
Prognosis
Proteins
Signal transduction
Tumorigenesis
Tumors
Wnt protein
β-Catenin
title Functional redundancy between Apc and Apc2 regulates tissue homeostasis and prevents tumorigenesis in murine mammary epithelium
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