Neutron-induced Rat Mammary Carcinomas Are Mainly of Luminal Subtype and Have Multiple Copy Number Aberrations

Abstract

to understand the subtype(s) of these carcinomas for which the incidence was increased following neutron exposure. We also clarified the DNA copy number aberrations of these mammary carcinomas to elucidate the mechanisms of neutron-induced carcinogenesis. Materials and Methods Tissue samples. Tumor samples were obtained from our previous study (8), which was approved by the Institutional Animal Care and Use Committee of National Institute of Radiological Sciences. Briefly, in that previous study, 7-week-old female Jcl:SD rats (Clea Japan Inc., Tokyo, Japan) were whole-body irradiated with 9 Be(d,nγ) 10 B fast neutrons (mean energy, 2 MeV) or 137 Cs γ rays, and mammary carcinoma development was assessed by weekly palpation until the age of 90 weeks. All of the carcinomas available from the neutron-irradiated (0.485 Gy, n=16), γ-ray-irradiated (0.5 Gy, n=14), and the matched untreated rats (n=28), excluding the ones from rats found dead, were analysed.

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

“…Third, it is unclear whether the mammary carcinoma subtype is strain-dependent. Our previous studies on mammary carcinomas of (SD×COP)F 1 (n = 24 tumors) and SD (n = 85 tumors) rats indicated that they are mainly (70%-90%) of the luminal subtype [22,32,33], consistent with reports from other laboratories [47,48]. Further studies are required to clarify if this applies to COP rats, as the number of tumors obtained in our study was small (n = 9) due to the high resistance of the strain.…”

“…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).…”

“…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%).…”

Modifiers of radiation effects on breast cancer incidence revealed by a reanalysis of archival data of rat experiments

“…The peripubertal peak of the age-at-exposure dependence suggests its association with the very rapid cell proliferation that occurs during puberty [ 26 ]. The genome of radiation-induced rat mammary cancer frequently displays large structural abnormalities [ 27–29 ], suggesting the influence of error-prone end-joining machinery. The effect of Brca1 knockout on radiation-induced mammary carcinogenesis was minimal in rats irradiated immediately after, but not before, puberty [ 30 ].…”

Neutron Radiobiology and Dosimetry

“…Stochastic effects, generally late effects such as carcinogenesis, are probabilistic in nature. Although the impact of neutrons on stochastic effects is not clear, the stochastic effects of neutrons and mixed-field exposures are being studied, as demonstrated by the available literature on carcinogenic effects of neutrons (37)(38)(39)(40). However, further research is needed to improve understanding of the risk associated with exposures below the level at which deterministic effects occur.…”