Radiation induces genomic instability and mammary ductal dysplasia in Atm heterozygous mice

Weil, Michael M.; Kittrell, Frances; Yu, Yongjia; McCarthy, Molly; Zabriskie, Ryan C.; Ullrich, Robert L.

doi:10.1038/sj.onc.1204589

Cited by 24 publications

(12 citation statements)

References 11 publications

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“…However, sensitivity to radiation-associated mammary ductal dysplasia (a precursor for tumors) has been confirmed in mice heterozygous for AT mutations [97]. Like AT, Nijmegen breakage syndrome is a rare recessive genetic disorder characterized by increased radiosensitivity and predisposition for lymphohematopoietic malignancies at young age [98].…”

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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Section: Modification Of Dose Responsementioning

confidence: 99%

Radiation and breast cancer: a review of current evidence

2004

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“…In a previous study, mammary gland epithelial cells of irradiated Atm ϩ/Ϫ mice were shown to develop ductal dysplasia when transplanted into syngenic recipients. However, cells isolated from unirradiated Atm ϩ/Ϫ mice formed normal ducts (5). In addition, whether exposed to radiations or not, mice carrying genetically engineered Atm inactivation fail to display an increased incidence of mammary gland carcinomas, reflecting potential differences in sensitivity, pathways of tumorigenesis, or mechanisms of ATM activation between the two species (1), thus making the relevance of these findings to the breast cancer susceptibility of A-T carriers unclear.…”

Section: Ataxia Telangiectasia (A-t)mentioning

confidence: 99%

Ataxia Telangiectasia Mutated (ATM) Inhibition Transforms Human Mammary Gland Epithelial Cells

Mandriota

Buser

Lesne

et al. 2010

Journal of Biological Chemistry

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Carriers of mutations in the cell cycle checkpoint protein kinase ataxia telangiectasia mutated (ATM), which represent 1-2% of the general population, have an increased risk of breast cancer. However, experimental evidence that ATM deficiency contributes to human breast carcinogenesis is lacking. We report here that in MCF-10A and MCF-12A cells, which are well established normal human mammary gland epithelial cell models, partial or almost complete stable ATM silencing or pharmacological inhibition resulted in cellular transformation, genomic instability, and formation of dysplastic lesions in NOD/ SCID mice. These effects did not require the activity of exogenous DNA-damaging agents and were preceded by an unsuspected and striking increase in cell proliferation also observed in primary human mammary gland epithelial cells. Increased proliferation correlated with a dramatic, transient, and proteasomedependent reduction of p21 WAF1/CIP1 and p27 KIP1 protein levels, whereas little or no effect was observed on p21 WAF1/CIP1 or p27 KIP1 mRNAs. p21 WAF1/CIP1 silencing also increased MCF-10A cell proliferation, thus identifying p21 WAF1/CIP1 down-regulation as a mediator of the proliferative effect of ATM inhibition. Our findings provide the first experimental evidence that ATM is a human breast tumor suppressor. In addition, they mirror the sensitivity of ATM tumor suppressor function and unveil a new mechanism by which ATM might prevent human breast tumorigenesis, namely a direct inhibitory effect on the basal proliferation of normal mammary epithelial cells.

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“…8 Heterozygous mice show increased cataract formation, 9 radiation-induced mammary ductal dysplasia (precursor to mammary cancer), 10 and increased susceptibility to cancer. 11 Ataxia telangiectasia cells are in a constant state of oxidative stress even in the absence of irradiation.…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress in ataxia telangiectasia

Watters

2003

Redox Report

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Ataxia telangiectasia is one of a group of recessive hereditary genomic instability disorders and is characterized by progressive neurodegeneration, immunodeficiency and cancer susceptibility. Heterozygotes for the mutated gene are more susceptible to cancer and to ischaemic heart disease. The affected gene, ATM (ataxia telangiectasia mutated), has been cloned and codes for a protein kinase (ATM), which orchestrates the cellular response to DNA double-strand breaks after ionising radiation. An underlying feature of ataxia telangiectasia is oxidative stress and there is chronic activation of stress response pathways in tissues showing pathology such as the cerebellum, but not in the cerebrum or liver. ATM has also been shown to be activated by insulin and to have a wider role in signal transduction and cell growth. Many, but not all, aspects of the phenotype can be attributed to a defective DNA damage response. The oxidative stress may result directly from accumulated DNA damage in affected tissues or ATM may have an additional role in sensing/modulating redox homeostasis. The basis for the observed tissue specificity of the oxidative damage in ataxia telangiectasia is not clear.

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Radiation induces genomic instability and mammary ductal dysplasia in Atm heterozygous mice

Cited by 24 publications

References 11 publications

Radiation and breast cancer: a review of current evidence

Radiation and breast cancer: a review of current evidence

Ataxia Telangiectasia Mutated (ATM) Inhibition Transforms Human Mammary Gland Epithelial Cells

Oxidative stress in ataxia telangiectasia

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