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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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 |
format | Article |
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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.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/onc.2016.342</identifier><identifier>PMID: 27694902</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>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</subject><ispartof>Oncogene, 2017-03, Vol.36 (13), p.1793-1803</ispartof><rights>The Author(s) 2017</rights><rights>COPYRIGHT 2017 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Mar 30, 2017</rights><rights>The Author(s) 2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Copyright © 2017 The Author(s) 2017 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c578t-bcfac2656c8999ece47de6f42adaa3da5d2ca93d7dd967c9b0f3a1ea4eb2d95f3</citedby><cites>FETCH-LOGICAL-c578t-bcfac2656c8999ece47de6f42adaa3da5d2ca93d7dd967c9b0f3a1ea4eb2d95f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,782,786,887,27931,27932</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27694902$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Daly, C S</creatorcontrib><creatorcontrib>Shaw, P</creatorcontrib><creatorcontrib>Ordonez, L D</creatorcontrib><creatorcontrib>Williams, G T</creatorcontrib><creatorcontrib>Quist, J</creatorcontrib><creatorcontrib>Grigoriadis, A</creatorcontrib><creatorcontrib>Van Es, J H</creatorcontrib><creatorcontrib>Clevers, H</creatorcontrib><creatorcontrib>Clarke, A R</creatorcontrib><creatorcontrib>Reed, K R</creatorcontrib><title>Functional redundancy between Apc and Apc2 regulates tissue homeostasis and prevents tumorigenesis in murine mammary epithelium</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><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.</description><subject>38</subject><subject>38/1</subject><subject>631/208/68</subject><subject>631/67/1347</subject><subject>631/67/68</subject><subject>64/60</subject><subject>82/51</subject><subject>Adenomatous polyposis coli</subject><subject>Adenomatous Polyposis Coli Protein - genetics</subject><subject>Adenomatous Polyposis Coli Protein - metabolism</subject><subject>Analysis</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>beta Catenin - genetics</subject><subject>beta Catenin - metabolism</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - mortality</subject><subject>Breast Neoplasms - pathology</subject><subject>Carcinogenesis</subject><subject>Carcinogenesis - genetics</subject><subject>Carcinogenesis - metabolism</subject><subject>Cell Biology</subject><subject>Cell division</subject><subject>Cell Transformation, Neoplastic - genetics</subject><subject>Cell Transformation, Neoplastic - metabolism</subject><subject>Cytoskeletal Proteins - genetics</subject><subject>Cytoskeletal Proteins - metabolism</subject><subject>DNA Copy Number Variations</subject><subject>Epithelium</subject><subject>Epithelium - metabolism</subject><subject>Epithelium - pathology</subject><subject>Female</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene Knockdown Techniques</subject><subject>Genetic disorders</subject><subject>Genetic regulation</subject><subject>Homeostasis</subject><subject>Homeostasis - genetics</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Hyperplasia</subject><subject>Internal Medicine</subject><subject>Lactation - genetics</subject><subject>Mammary gland</subject><subject>Mammary Neoplasms, Animal</subject><subject>Medical prognosis</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Oncology</subject><subject>Original</subject><subject>original-article</subject><subject>Phenotypes</subject><subject>Physiological aspects</subject><subject>Polyposis coli</subject><subject>Prognosis</subject><subject>Proteins</subject><subject>Signal transduction</subject><subject>Tumorigenesis</subject><subject>Tumors</subject><subject>Wnt 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redundancy between Apc and Apc2 regulates tissue homeostasis and prevents tumorigenesis in murine mammary epithelium</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c578t-bcfac2656c8999ece47de6f42adaa3da5d2ca93d7dd967c9b0f3a1ea4eb2d95f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>38</topic><topic>38/1</topic><topic>631/208/68</topic><topic>631/67/1347</topic><topic>631/67/68</topic><topic>64/60</topic><topic>82/51</topic><topic>Adenomatous polyposis coli</topic><topic>Adenomatous Polyposis Coli Protein - genetics</topic><topic>Adenomatous Polyposis Coli Protein - metabolism</topic><topic>Analysis</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>beta Catenin - genetics</topic><topic>beta Catenin - metabolism</topic><topic>Breast cancer</topic><topic>Breast Neoplasms - genetics</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - mortality</topic><topic>Breast Neoplasms - pathology</topic><topic>Carcinogenesis</topic><topic>Carcinogenesis - genetics</topic><topic>Carcinogenesis - metabolism</topic><topic>Cell Biology</topic><topic>Cell division</topic><topic>Cell Transformation, Neoplastic - genetics</topic><topic>Cell Transformation, Neoplastic - metabolism</topic><topic>Cytoskeletal Proteins - genetics</topic><topic>Cytoskeletal Proteins - metabolism</topic><topic>DNA Copy Number Variations</topic><topic>Epithelium</topic><topic>Epithelium - metabolism</topic><topic>Epithelium - pathology</topic><topic>Female</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Gene Knockdown Techniques</topic><topic>Genetic disorders</topic><topic>Genetic regulation</topic><topic>Homeostasis</topic><topic>Homeostasis - genetics</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Hyperplasia</topic><topic>Internal Medicine</topic><topic>Lactation - genetics</topic><topic>Mammary gland</topic><topic>Mammary Neoplasms, Animal</topic><topic>Medical prognosis</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Oncology</topic><topic>Original</topic><topic>original-article</topic><topic>Phenotypes</topic><topic>Physiological aspects</topic><topic>Polyposis coli</topic><topic>Prognosis</topic><topic>Proteins</topic><topic>Signal transduction</topic><topic>Tumorigenesis</topic><topic>Tumors</topic><topic>Wnt protein</topic><topic>β-Catenin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Daly, C S</creatorcontrib><creatorcontrib>Shaw, P</creatorcontrib><creatorcontrib>Ordonez, L D</creatorcontrib><creatorcontrib>Williams, G T</creatorcontrib><creatorcontrib>Quist, 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Central Basic</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Daly, C S</au><au>Shaw, P</au><au>Ordonez, L D</au><au>Williams, G T</au><au>Quist, J</au><au>Grigoriadis, A</au><au>Van Es, J H</au><au>Clevers, H</au><au>Clarke, A R</au><au>Reed, K R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Functional redundancy between Apc and Apc2 regulates tissue homeostasis and prevents tumorigenesis in murine mammary epithelium</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2017-03-30</date><risdate>2017</risdate><volume>36</volume><issue>13</issue><spage>1793</spage><epage>1803</epage><pages>1793-1803</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><coden>ONCNES</coden><abstract>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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>27694902</pmid><doi>10.1038/onc.2016.342</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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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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