Age and Radiation Sensitivity of Rat Mammary Clonogenic Cells

Shimada, Yoshiya; Yasukawa-Barnes, Jane; Kim, Richard; Gould, Michael N.; Clifton, Kelly H.

doi:10.2307/3578800

Cited by 22 publications

(12 citation statements)

References 18 publications

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“…Clonogenicity of mammary epithelial cells in culture is highly species- and assay-dependent, and difficult to extrapolate between mouse, rat and human. However, a previous study of rat mammary epithelial cell populations suggested that clonogens were only radiosensitive in pre-pubertal development (a result that would correspond to the one reported here) [37], and also showed that the response of clonogenic cells was different for mutagens that did not induce double strand breaks [38].…”

Section: Discussionsupporting

confidence: 84%

Genotoxic Exposure during Juvenile Growth of Mammary Gland Depletes Stem Cell Activity and Inhibits Wnt Signaling

2012

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Various types of somatic stem cell have been tested for their response to genotoxic exposure, since these cells are likely to be important to regeneration, aging and cancer. In this study, we evaluated the response of mammary stem cells to genotoxic exposure during ductal growth in juveniles. Exposure to the polycyclic aromatic hydrocarbon (DMBA; 7,12 dimethylbenz[a]anthracene) had no gross effect on outgrowth and morphogenesis of the ductal tree, or upon lobuloalveolar growth during pregnancy. However, by fat pad assay, we found that mammary stem cell activity was reduced by 80% in glands from adults that were exposed to genotoxins as juveniles. The associated basal cell lineage was depleted. Both basal and luminal cells showed a robust response to genotoxic exposure (including γH2AX phosphorylation, pS15p53 and pT68Chk2), with durable hyperproliferation, but little cytotoxicity. Since the phenotype of these glands (low basal cell fraction, low stem cell activity) phenocopies mammary glands with loss of function for Wnt signaling, we measured Wnt signaling in genotoxin-exposed glands, and found a durable reduction in the activation of the canonical signaling Wnt receptors, Lrp5/6. Furthermore, when mammary epithelial cells were treated with Wnt3a, DMBA exposure reduced the basal cell population and Lrp activation was ablated. We conclude that during active ductal growth, Wnt-dependent mammary stem cells are sensitized to cell death by genotoxin exposure. Our conclusion may be important for other tissues, since all solid tumor stem cell activities have been shown to be Wnt-dependent to date.

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Section: Discussionsupporting

confidence: 84%

Genotoxic Exposure during Juvenile Growth of Mammary Gland Depletes Stem Cell Activity and Inhibits Wnt Signaling

2012

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“…Stem and progenitor cells constitute a small undifferentiated subpopulation of breast tissue and are the proposed cells of origin of breast cancer [47]. These cells are initially quiescent but begin to proliferate during and after puberty [48]. They have a basal‐like phenotype, and because they lack ovarian hormone receptors they depend on ErbB signaling, probably via the paracrine action of estrogen‐induced amphiregulin [47].…”

Section: Discussionmentioning

confidence: 99%

Pre‐ and postpubertal irradiation induces mammary cancers with distinct expression of hormone receptors, ErbB ligands, and developmental genes in rats

Imaoka¹,

Nishimura²,

Iizuka

et al. 2011

Molecular Carcinogenesis

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Childhood exposure to carcinogens renders a higher risk of breast cancer. The molecular mechanisms underlying cancer development after such exposure are not, however, well understood. Here we examined how the mechanism of cancer development relates to the age at exposure to ionizing radiation (IR) or the carcinogen 1-methyl-1-nitrosourea (MNU). Pre- and postpubertal (3- and 7-wk-old, respectively) female Sprague-Dawley rats were whole-body γ-irradiated (2 Gy), injected intraperitoneally with MNU (20 mg/kg) or left untreated and were autopsied at 50 wk of age. Mammary carcinomas were examined for estrogen receptor (ER) α, progesterone receptor (PR) and ErbB ligand expression and for expression microarrays. Early histological changes of the ovaries were also evaluated. The incidence of mammary cancer was higher after postpubertal, rather than prepubertal, IR exposure; the inverse was true for MNU. Most cancers were positive for both ERα and PR except for the prepubertal IR group. Cancers of the prepubertal IR group expressed a different set of ErbB ligands from those of the other groups and did not overexpress Areg, which encodes an estrogen-regulated ErbB ligand, or other developmentally related genes including those for hormonally regulated mammary gland development. Prepubertal IR exposure resulted in ovarian dysfunction as revealed by a reduced follicular pool. Evidence thus suggests that mammary carcinogenesis induced by prepubertal IR exposure is independent of ovarian hormones but requires certain ErbB ligands; induction by postpubertal exposure depends on ovarian hormones and different ErbB ligands. In contrast, the mechanism of MNU-induced carcinogenesis was less influenced by the age at exposure.

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“…Shimada and colleagues [72] proposed that prepubertal rats are more sensitive to radiation-associated cell killing than older animals because of a relative lack of DNA repair before puberty. In contrast, one of the only studies that included rats (Sprague–Daley) exposed before puberty showed less adenocarcinoma than those exposed at later ages (42–225 days) [73].…”

Section: Modification Of Dose Responsementioning

confidence: 99%

Radiation and breast cancer: a review of current evidence

2004

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21AT = ataxia-telangiectasia; ATM = ataxia telangiectasia mutated; BBD = benign breast disease; DSB = double-strand break; EAR = excess absolute risk; ERR = excess relative risk; FFTP = first full-term pregnancy; HL = Hodgkin lymphoma; LSS = Life Span Study; NHEJ = non-homologous end joining.Available online http://breast-cancer-research.com/content/7/1/21 IntroductionThe mammary gland is very sensitive to radiationassociated carcinogenesis, especially after exposures at young ages. Many aspects of the association between radiation and breast cancer have been elucidated in the past decades. This review is intended to summarize widely recognized features of radiation-associated breast cancer and to add a more detailed overview of relevant recent findings, especially focusing on factors that modify the radiation-related risk. Epidemiology of breast cancerIn 2000, breast cancer was the most common malignant disease in women worldwide, with an estimated 1.05 million cases. Owing to high levels of screening in developed countries and the relatively favorable prognosis of early-stage disease, it is also the most prevalent malignancy in women, with almost 4 million women alive who have had breast cancer in the past 5 years [1]. In the USA, it is estimated that about 216,000 women will be diagnosed with breast cancer in 2004 and that 40,000 will die from the disease [2]. Male breast cancer is a rare disease, with an incidence about 1/100 of that for female breast cancer [2].Breast cancer is very rare before age 30 years, after which incidence rises steeply with advancing age up to about age 50 years. Thereafter, incidence still increases with age, but more slowly [3]. The strong dependence on age, as seen for many other adult-type cancers, is probably related to accumulating genetic damage that occurs during a human lifespan. The apparent change in slope of the age-incidence curve at about age 50 years is unique for breast cancer, and this is presumably related to hormonal changes associated with menopause, which is accompanied by a decrease in circulating estrogen levels AbstractThis paper summarizes current knowledge on ionizing radiation-associated breast cancer in the context of established breast cancer risk factors, the radiation dose-response relationship, and modifiers of dose response, taking into account epidemiological studies and animal experiments. Available epidemiological data support a linear dose-response relationship down to doses as low as about 100 mSv. However, the magnitude of risk per unit dose depends strongly on when radiation exposure occurs: exposure before the age of 20 years carries the greatest risk. Other characteristics that may influence the magnitude of dose-specific risk include attained age (that is, age at observation for risk), age at first full-term birth, parity, and possibly a history of benign breast disease, exposure to radiation while pregnant, and genetic factors.

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Age and Radiation Sensitivity of Rat Mammary Clonogenic Cells

Cited by 22 publications

References 18 publications

Genotoxic Exposure during Juvenile Growth of Mammary Gland Depletes Stem Cell Activity and Inhibits Wnt Signaling

Genotoxic Exposure during Juvenile Growth of Mammary Gland Depletes Stem Cell Activity and Inhibits Wnt Signaling

Pre‐ and postpubertal irradiation induces mammary cancers with distinct expression of hormone receptors, ErbB ligands, and developmental genes in rats

Radiation and breast cancer: a review of current evidence

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