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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Autores principales:	Mayumi Nishimura, Kazuhiro Daino, Maki Fukuda, Ikuya Tanaka, Hitomi Moriyama, Kaye Showler, Yukiko Nishimura, Masaru Takabatake, Toshiaki Kokubo, Atsuko Ishikawa, Kazumasa Inoue, Masahiro Fukushi, Shizuko Kakinuma, Tatsuhiko Imaoka, Yoshiya Shimada
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f809fc58fb0444b397ec183fc7dd069b
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spelling	oai:doaj.org-article:f809fc58fb0444b397ec183fc7dd069b2021-12-02T20:18:09ZDevelopment 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.1932-620310.1371/journal.pone.0255968https://doaj.org/article/f809fc58fb0444b397ec183fc7dd069b2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0255968https://doaj.org/toc/1932-6203Copenhagen 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.Mayumi NishimuraKazuhiro DainoMaki FukudaIkuya TanakaHitomi MoriyamaKaye ShowlerYukiko NishimuraMasaru TakabatakeToshiaki KokuboAtsuko IshikawaKazumasa InoueMasahiro FukushiShizuko KakinumaTatsuhiko ImaokaYoshiya ShimadaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 8, p e0255968 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mayumi Nishimura Kazuhiro Daino Maki Fukuda Ikuya Tanaka Hitomi Moriyama Kaye Showler Yukiko Nishimura Masaru Takabatake Toshiaki Kokubo Atsuko Ishikawa Kazumasa Inoue Masahiro Fukushi Shizuko Kakinuma Tatsuhiko Imaoka Yoshiya Shimada 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.
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.
format	article
author	Mayumi Nishimura Kazuhiro Daino Maki Fukuda Ikuya Tanaka Hitomi Moriyama Kaye Showler Yukiko Nishimura Masaru Takabatake Toshiaki Kokubo Atsuko Ishikawa Kazumasa Inoue Masahiro Fukushi Shizuko Kakinuma Tatsuhiko Imaoka Yoshiya Shimada
author_facet	Mayumi Nishimura Kazuhiro Daino Maki Fukuda Ikuya Tanaka Hitomi Moriyama Kaye Showler Yukiko Nishimura Masaru Takabatake Toshiaki Kokubo Atsuko Ishikawa Kazumasa Inoue Masahiro Fukushi Shizuko Kakinuma Tatsuhiko Imaoka Yoshiya Shimada
author_sort	Mayumi Nishimura
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_short	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_full	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_fullStr	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_full_unstemmed	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_sort	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.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/f809fc58fb0444b397ec183fc7dd069b
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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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