Exome of Radiation-induced Rat Mammary Carcinoma Shows Copy-number Losses and Mutations in Human-relevant Cancer Genes

Moriyama, Hitomi; Daino, Kazuhiro; Ishikawa, Atsuko; Imaoka, Tatsuhiko; Nishimura, Masaharu; Nishimura, Yukiko; Takabatake, Masaru; Morioka, Takamitsu; Inoue, Kazuaki; Fukushi, Masahiro; Shimada, Yoshiya; Kakinuma, Shizuko

doi:10.21873/anticanres.14751

Cited by 6 publications

(15 citation statements)

References 17 publications

(23 reference statements)

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“…Previous studies have shown that radiation-induced mammary carcinomas of SD rats harbor multiple copy-number aberrations that do not converge to specific chromosomal regions [26,32,33]. In surprising contrast, our present analysis of mammary carcinomas (n = 21) from (SD×COP)F 1 rats revealed multiple copy-number variations in several specific chromosomal regions (Fig 2A).…”

Section: Mammary Carcinomas Of (Sd×cop) F 1 Rats Have Multiple Localized Copynumber Variationscontrasting

confidence: 68%

“…Interestingly, the number of genes affected by copy-number loss was positively correlated with age at tumor detection (Fig 2B, P < 0.01), which could be explained by correlation with the number of chromosomes with large deletions spanning >80% of the chromosome (Fig 2C, P < 0.01). The frequencies of copy-number losses and gains involving human-relevant tumor suppressors and proto-oncogenes, respectively, were much higher than those reported in a previous study on SD rats [33] (Table 6, two rightmost columns).…”

Section: Plos Onecontrasting

confidence: 67%

“…Additional large deletions spanning nearly all of chromosome 5 were identified in 6 carcinomas (29%). Focal deletions involving Cdkn2a and Cdkn2b were found at chromosome 5q32 in 2 carcinomas (10%), as had been repeatedly observed in a subset of radiation-induced rat mammary carcinomas [26,32,33]. Combined, focal and large deletions affected this chromosomal region in 8 carcinomas (38%).…”

Section: Mammary Carcinomas Of (Sd×cop) F 1 Rats Have Multiple Localized Copynumber Variationssupporting

confidence: 53%

“…and 3q31-42 as well as chromosome 5, with many genes in these regions showing reduced expression. This frequency is higher than the AI frequency reported in radiation-induced mammary cancer of (WF×COP)F 1 rats (4-13%) [18], and higher than the frequency of copy number changes in breast cancer-relevant genes in SD rats (4-11%) [33]. Thus, (SD×COP)F 1 rats offer a new option in the search for causative genes of radiation-induced mammary cancer.…”

Section: Plos Onementioning

confidence: 60%

“…We examined the mammary-cancer susceptibility of irradiated (SD×COP)F 1 hybrids of susceptible SD and resistant COP rats and found that they had intermediate susceptibility levels; thus, they are useful for exploring cancer-causing gene mutations. Our approach of combining analyses of copy-number variations and AIs in mammary cancer successfully identified marginally frequent (14-38%) copy-number losses in chromosome regions 1q52-54, 2q12-15, Includes γ-ray-induced (n = 10), neutron-induced (n = 8) and sporadic (n = 10) mammary carcinomas in SD rats [33];…”

Section: Discussionmentioning

confidence: 99%

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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

et al. 2021

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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.

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Section: Mammary Carcinomas Of (Sd×cop) F 1 Rats Have Multiple Localized Copynumber Variationscontrasting

confidence: 68%

Section: Plos Onecontrasting

confidence: 67%

Section: Mammary Carcinomas Of (Sd×cop) F 1 Rats Have Multiple Localized Copynumber Variationssupporting

confidence: 53%

Section: Plos Onementioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

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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

et al. 2021

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Induced mammary cancer in rat models: pathogenesis, genetics, and relevance to female breast cancer

Miller

Bartlett

Harman

et al. 2022

J Mammary Gland Biol Neoplasia

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Rat Models of Hormone Receptor-Positive Breast Cancer

Nicotra,

Lutz,

Messal

et al. 2024

J Mammary Gland Biol Neoplasia

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Hormone receptor-positive (HR+) breast cancer (BC) is the most common type of breast cancer among women worldwide, accounting for 70–80% of all invasive cases. Patients with HR+ BC are commonly treated with endocrine therapy, but intrinsic or acquired resistance is a frequent problem, making HR+ BC a focal point of intense research. Despite this, the malignancy still lacks adequate in vitro and in vivo models for the study of its initiation and progression as well as response and resistance to endocrine therapy. No mouse models that fully mimic the human disease are available, however rat mammary tumor models pose a promising alternative to overcome this limitation. Compared to mice, rats are more similar to humans in terms of mammary gland architecture, ductal origin of neoplastic lesions and hormone dependency status. Moreover, rats can develop spontaneous or induced mammary tumors that resemble human HR+ BC. To date, six different types of rat models of HR+ BC have been established. These include the spontaneous, carcinogen-induced, transplantation, hormone-induced, radiation-induced and genetically engineered rat mammary tumor models. Each model has distinct advantages, disadvantages and utility for studying HR+ BC. This review provides a comprehensive overview of all published models to date.

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Exome of Radiation-induced Rat Mammary Carcinoma Shows Copy-number Losses and Mutations in Human-relevant Cancer Genes

Cited by 6 publications

References 17 publications

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

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

Induced mammary cancer in rat models: pathogenesis, genetics, and relevance to female breast cancer

Rat Models of Hormone Receptor-Positive Breast Cancer

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