Development of mammary cancer in γ-irradiated F1 hybrids of susceptible Sprague-Dawley and resistant Copenhagen rats, with copy-number losses that pinpoint potential tumor suppressors
Copenhagen rats are highly resistant to mammary carcinogenesis, even after treatment with chemical carcinogens and hormones; most studies indicate that this is a dominant genetic trait. To test whether this trait is also dominant after radiation exposure, we characterized the susceptibility of irrad...
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| creator | Nishimura, Mayumi Daino, Kazuhiro Fukuda, Maki Tanaka, Ikuya Moriyama, Hitomi Showler, Kaye Nishimura, Yukiko Takabatake, Masaru Kokubo, Toshiaki Ishikawa, Atsuko Inoue, Kazumasa Fukushi, Masahiro Kakinuma, Shizuko Imaoka, Tatsuhiko Shimada, Yoshiya |
| description | Copenhagen rats are highly resistant to mammary carcinogenesis, even after treatment with chemical carcinogens and hormones; most studies indicate that this is a dominant genetic trait. To test whether this trait is also dominant after radiation exposure, we characterized the susceptibility of irradiated Copenhagen rats to mammary carcinogenesis, as well as its inheritance, and identified tumor-suppressor genes that, when inactivated or mutated, may contribute to carcinogenesis. To this end, mammary cancer-susceptible Sprague-Dawley rats, resistant Copenhagen rats, and their F1 hybrids were irradiated with 4 Gy of γ-rays, and tumor development was monitored. Copy-number variations and allelic imbalances of genomic DNA were studied using microarrays and PCR analysis of polymorphic markers. Gene expression was assessed by quantitative PCR in normal tissues and induced mammary cancers of F1 rats. Irradiated Copenhagen rats exhibited a very low incidence of mammary cancer. Unexpectedly, this resistance trait did not show dominant inheritance in F1 rats; rather, they exhibited intermediate susceptibility levels (i.e., between those of their parent strains). The susceptibility of irradiated F1 rats to the development of benign mammary tumors (i.e., fibroadenoma and adenoma) was also intermediate. Copy-number losses were frequently observed in chromosome regions 1q52-54 (24%), 2q12-15 (33%), and 3q31-42 (24%), as were focal (38%) and whole (29%) losses of chromosome 5. Some of these chromosomal regions exhibited allelic imbalances. Many cancer-related genes within these regions were downregulated in mammary tumors as compared with normal mammary tissue. Some of the chromosomal losses identified have not been reported previously in chemically induced models, implying a novel mechanism inherent to the irradiated model. Based on these findings, Sprague-Dawley × Copenhagen F1 rats offer a useful model for exploring genes responsible for radiation-induced mammary cancer, which apparently are mainly located in specific regions of chromosomes 1, 2, 3 and 5. |
| doi_str_mv | 10.1371/journal.pone.0255968 |
| format | Article |
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To test whether this trait is also dominant after radiation exposure, we characterized the susceptibility of irradiated Copenhagen rats to mammary carcinogenesis, as well as its inheritance, and identified tumor-suppressor genes that, when inactivated or mutated, may contribute to carcinogenesis. To this end, mammary cancer-susceptible Sprague-Dawley rats, resistant Copenhagen rats, and their F1 hybrids were irradiated with 4 Gy of γ-rays, and tumor development was monitored. Copy-number variations and allelic imbalances of genomic DNA were studied using microarrays and PCR analysis of polymorphic markers. Gene expression was assessed by quantitative PCR in normal tissues and induced mammary cancers of F1 rats. Irradiated Copenhagen rats exhibited a very low incidence of mammary cancer. Unexpectedly, this resistance trait did not show dominant inheritance in F1 rats; rather, they exhibited intermediate susceptibility levels (i.e., between those of their parent strains). The susceptibility of irradiated F1 rats to the development of benign mammary tumors (i.e., fibroadenoma and adenoma) was also intermediate. Copy-number losses were frequently observed in chromosome regions 1q52-54 (24%), 2q12-15 (33%), and 3q31-42 (24%), as were focal (38%) and whole (29%) losses of chromosome 5. Some of these chromosomal regions exhibited allelic imbalances. Many cancer-related genes within these regions were downregulated in mammary tumors as compared with normal mammary tissue. Some of the chromosomal losses identified have not been reported previously in chemically induced models, implying a novel mechanism inherent to the irradiated model. Based on these findings, Sprague-Dawley × Copenhagen F1 rats offer a useful model for exploring genes responsible for radiation-induced mammary cancer, which apparently are mainly located in specific regions of chromosomes 1, 2, 3 and 5.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0255968</identifier><identifier>PMID: 34388197</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenoma ; Animals ; Auroral kilometric radiation ; Biology and Life Sciences ; Breast cancer ; Cancer ; Carcinogenesis ; Carcinogens ; Chromosome 5 ; Chromosome Aberrations ; Chromosomes ; Deoxyribonucleic acid ; Disease Models, Animal ; DNA ; DNA Copy Number Variations ; DNA microarrays ; Environmental science ; Experiments ; Female ; Fibroadenoma ; Funding ; Gamma rays ; Gamma Rays - adverse effects ; Gene expression ; Gene Expression Regulation, Neoplastic ; Genes ; Genes, Tumor Suppressor ; Genetic Predisposition to Disease ; Heredity ; Hormones ; Hospitals ; Hybrids ; Laboratory animals ; Mammary Neoplasms, Experimental - etiology ; Mammary Neoplasms, Experimental - metabolism ; Mammary Neoplasms, Experimental - pathology ; Medical research ; Medicine and Health Sciences ; Mutation ; Polymerase chain reaction ; Radiation ; Radiation effects ; Rats ; Rats, Sprague-Dawley ; Research and Analysis Methods ; Supervision ; Suppressors ; Tumor suppressor genes ; Tumors</subject><ispartof>PloS one, 2021-01, Vol.16 (8), p.e0255968</ispartof><rights>2021 Nishimura et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 Nishimura et al 2021 Nishimura et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c500t-eb1f30dc89160e5f1303d194e6cb8a8af0c3c294c003666510206d1521aeeff43</citedby><cites>FETCH-LOGICAL-c500t-eb1f30dc89160e5f1303d194e6cb8a8af0c3c294c003666510206d1521aeeff43</cites><orcidid>0000-0003-1507-585X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362979/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362979/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34388197$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nishimura, Mayumi</creatorcontrib><creatorcontrib>Daino, Kazuhiro</creatorcontrib><creatorcontrib>Fukuda, Maki</creatorcontrib><creatorcontrib>Tanaka, Ikuya</creatorcontrib><creatorcontrib>Moriyama, Hitomi</creatorcontrib><creatorcontrib>Showler, Kaye</creatorcontrib><creatorcontrib>Nishimura, Yukiko</creatorcontrib><creatorcontrib>Takabatake, Masaru</creatorcontrib><creatorcontrib>Kokubo, Toshiaki</creatorcontrib><creatorcontrib>Ishikawa, Atsuko</creatorcontrib><creatorcontrib>Inoue, Kazumasa</creatorcontrib><creatorcontrib>Fukushi, Masahiro</creatorcontrib><creatorcontrib>Kakinuma, Shizuko</creatorcontrib><creatorcontrib>Imaoka, Tatsuhiko</creatorcontrib><creatorcontrib>Shimada, Yoshiya</creatorcontrib><title>Development of mammary cancer in γ-irradiated F1 hybrids of susceptible Sprague-Dawley and resistant Copenhagen rats, with copy-number losses that pinpoint potential tumor suppressors</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Copenhagen rats are highly resistant to mammary carcinogenesis, even after treatment with chemical carcinogens and hormones; most studies indicate that this is a dominant genetic trait. To test whether this trait is also dominant after radiation exposure, we characterized the susceptibility of irradiated Copenhagen rats to mammary carcinogenesis, as well as its inheritance, and identified tumor-suppressor genes that, when inactivated or mutated, may contribute to carcinogenesis. To this end, mammary cancer-susceptible Sprague-Dawley rats, resistant Copenhagen rats, and their F1 hybrids were irradiated with 4 Gy of γ-rays, and tumor development was monitored. Copy-number variations and allelic imbalances of genomic DNA were studied using microarrays and PCR analysis of polymorphic markers. Gene expression was assessed by quantitative PCR in normal tissues and induced mammary cancers of F1 rats. Irradiated Copenhagen rats exhibited a very low incidence of mammary cancer. Unexpectedly, this resistance trait did not show dominant inheritance in F1 rats; rather, they exhibited intermediate susceptibility levels (i.e., between those of their parent strains). The susceptibility of irradiated F1 rats to the development of benign mammary tumors (i.e., fibroadenoma and adenoma) was also intermediate. Copy-number losses were frequently observed in chromosome regions 1q52-54 (24%), 2q12-15 (33%), and 3q31-42 (24%), as were focal (38%) and whole (29%) losses of chromosome 5. Some of these chromosomal regions exhibited allelic imbalances. Many cancer-related genes within these regions were downregulated in mammary tumors as compared with normal mammary tissue. Some of the chromosomal losses identified have not been reported previously in chemically induced models, implying a novel mechanism inherent to the irradiated model. Based on these findings, Sprague-Dawley × Copenhagen F1 rats offer a useful model for exploring genes responsible for radiation-induced mammary cancer, which apparently are mainly located in specific regions of chromosomes 1, 2, 3 and 5.</description><subject>Adenoma</subject><subject>Animals</subject><subject>Auroral kilometric radiation</subject><subject>Biology and Life Sciences</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Carcinogenesis</subject><subject>Carcinogens</subject><subject>Chromosome 5</subject><subject>Chromosome Aberrations</subject><subject>Chromosomes</subject><subject>Deoxyribonucleic acid</subject><subject>Disease Models, Animal</subject><subject>DNA</subject><subject>DNA Copy Number Variations</subject><subject>DNA microarrays</subject><subject>Environmental science</subject><subject>Experiments</subject><subject>Female</subject><subject>Fibroadenoma</subject><subject>Funding</subject><subject>Gamma rays</subject><subject>Gamma Rays - 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BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nishimura, Mayumi</au><au>Daino, Kazuhiro</au><au>Fukuda, Maki</au><au>Tanaka, Ikuya</au><au>Moriyama, Hitomi</au><au>Showler, Kaye</au><au>Nishimura, Yukiko</au><au>Takabatake, Masaru</au><au>Kokubo, Toshiaki</au><au>Ishikawa, Atsuko</au><au>Inoue, Kazumasa</au><au>Fukushi, Masahiro</au><au>Kakinuma, Shizuko</au><au>Imaoka, Tatsuhiko</au><au>Shimada, Yoshiya</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Development of mammary cancer in γ-irradiated F1 hybrids of susceptible Sprague-Dawley and resistant Copenhagen rats, with copy-number losses that pinpoint potential tumor suppressors</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2021-01-01</date><risdate>2021</risdate><volume>16</volume><issue>8</issue><spage>e0255968</spage><pages>e0255968-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Copenhagen rats are highly resistant to mammary carcinogenesis, even after treatment with chemical carcinogens and hormones; most studies indicate that this is a dominant genetic trait. To test whether this trait is also dominant after radiation exposure, we characterized the susceptibility of irradiated Copenhagen rats to mammary carcinogenesis, as well as its inheritance, and identified tumor-suppressor genes that, when inactivated or mutated, may contribute to carcinogenesis. To this end, mammary cancer-susceptible Sprague-Dawley rats, resistant Copenhagen rats, and their F1 hybrids were irradiated with 4 Gy of γ-rays, and tumor development was monitored. Copy-number variations and allelic imbalances of genomic DNA were studied using microarrays and PCR analysis of polymorphic markers. Gene expression was assessed by quantitative PCR in normal tissues and induced mammary cancers of F1 rats. Irradiated Copenhagen rats exhibited a very low incidence of mammary cancer. Unexpectedly, this resistance trait did not show dominant inheritance in F1 rats; rather, they exhibited intermediate susceptibility levels (i.e., between those of their parent strains). The susceptibility of irradiated F1 rats to the development of benign mammary tumors (i.e., fibroadenoma and adenoma) was also intermediate. Copy-number losses were frequently observed in chromosome regions 1q52-54 (24%), 2q12-15 (33%), and 3q31-42 (24%), as were focal (38%) and whole (29%) losses of chromosome 5. Some of these chromosomal regions exhibited allelic imbalances. Many cancer-related genes within these regions were downregulated in mammary tumors as compared with normal mammary tissue. Some of the chromosomal losses identified have not been reported previously in chemically induced models, implying a novel mechanism inherent to the irradiated model. Based on these findings, Sprague-Dawley × Copenhagen F1 rats offer a useful model for exploring genes responsible for radiation-induced mammary cancer, which apparently are mainly located in specific regions of chromosomes 1, 2, 3 and 5.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>34388197</pmid><doi>10.1371/journal.pone.0255968</doi><orcidid>https://orcid.org/0000-0003-1507-585X</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2021-01, Vol.16 (8), p.e0255968 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2561075171 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Adenoma Animals Auroral kilometric radiation Biology and Life Sciences Breast cancer Cancer Carcinogenesis Carcinogens Chromosome 5 Chromosome Aberrations Chromosomes Deoxyribonucleic acid Disease Models, Animal DNA DNA Copy Number Variations DNA microarrays Environmental science Experiments Female Fibroadenoma Funding Gamma rays Gamma Rays - adverse effects Gene expression Gene Expression Regulation, Neoplastic Genes Genes, Tumor Suppressor Genetic Predisposition to Disease Heredity Hormones Hospitals Hybrids Laboratory animals Mammary Neoplasms, Experimental - etiology Mammary Neoplasms, Experimental - metabolism Mammary Neoplasms, Experimental - pathology Medical research Medicine and Health Sciences Mutation Polymerase chain reaction Radiation Radiation effects Rats Rats, Sprague-Dawley Research and Analysis Methods Supervision Suppressors Tumor suppressor genes Tumors |
| title | Development of mammary cancer in γ-irradiated F1 hybrids of susceptible Sprague-Dawley and resistant Copenhagen rats, with copy-number losses that pinpoint potential tumor suppressors |
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