Induction of Mammary Tumors in Rats by Single-Dose Gamma Irradiation at Different Ages

Bartstra, R. W.; Bentvelzen, P.; Zoetelief, J.; Mulder, A. H.; Broerse, J.J.; Bekkum, D. W. van

doi:10.2307/3579664

Cited by 18 publications

(5 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Younger age of exposure, exposure to estrogen and progesterone, pregnancy, and genetic susceptibility influence breast cancer risk from IR in people (Berrington de Gonzalez et al 2010;Boice et al 1991;Land et al 2003;Ma et al 2008;Miller et al 1989;Preston et al 2007;Stovall et al 2008). In rodents, risk is highest for IR exposures during mammary gland development and puberty (Imaoka et al 2011(Imaoka et al , 2013(Imaoka et al , 2017 and lower for embryonic, adult (Imaoka et al 2011(Imaoka et al , 2013, and post-estrous rats (Bartstra et al 1998).…”

Section: Breast Cancer Risk Factorsmentioning

confidence: 99%

Adverse outcome pathways for ionizing radiation and breast cancer involve direct and indirect DNA damage, oxidative stress, inflammation, genomic instability, and interaction with hormonal regulation of the breast

Helm

Rudel

2020

Arch Toxicol

View full text Add to dashboard Cite

Knowledge about established breast carcinogens can support improved and modernized toxicological testing methods by identifying key mechanistic events. Ionizing radiation (IR) increases the risk of breast cancer, especially for women and for exposure at younger ages, and evidence overall supports a linear dose-response relationship. We used the Adverse Outcome Pathway (AOP) framework to outline and evaluate the evidence linking ionizing radiation with breast cancer from molecular initiating events to the adverse outcome through intermediate key events, creating a qualitative AOP. We identified key events based on review articles, searched PubMed for recent literature on key events and IR, and identified additional papers using references. We manually curated publications and evaluated data quality. Ionizing radiation directly and indirectly causes DNA damage and increases production of reactive oxygen and nitrogen species (RONS). RONS lead to DNA damage and epigenetic changes leading to mutations and genomic instability (GI). Proliferation amplifies the effects of DNA damage and mutations leading to the AO of breast cancer. Separately, RONS and DNA damage also increase inflammation. Inflammation contributes to direct and indirect effects (effects in cells not directly reached by IR) via positive feedback to RONS and DNA damage, and separately increases proliferation and breast cancer through pro-carcinogenic effects on cells and tissue. For example, gene expression changes alter inflammatory mediators, resulting in improved survival and growth of cancer cells and a more hospitable tissue environment. All of these events overlap at multiple points with events characteristic of "background" induction of breast carcinogenesis, including hormone-responsive proliferation, oxidative activity, and DNA damage. These overlaps make the breast particularly susceptible to ionizing radiation and reinforce that these biological activities are important characteristics of carcinogens. Agents that increase these biological processes should be considered potential breast carcinogens, and predictive methods are needed to identify chemicals that increase these processes. Techniques are available to measure RONS, DNA damage and mutation, cell proliferation, and some inflammatory proteins or processes. Improved assays are needed to measure GI and chronic inflammation, as well as the interaction with hormonally driven development and proliferation. Several methods measure diverse epigenetic changes, but it is not clear which changes are relevant to breast cancer. In addition, most toxicological assays are not conducted in mammary tissue, and so it is a priority to evaluate if results from other tissues are generalizable to breast, or to conduct assays in breast tissue. Developing and applying these assays to identify exposures of concern will facilitate efforts to reduce subsequent breast cancer risk.Biological systems studied This review article summarizes and synthesizes data from cell-culture, experimental animals, and human epidem...

show abstract

Section: Breast Cancer Risk Factorsmentioning

confidence: 99%

Adverse outcome pathways for ionizing radiation and breast cancer involve direct and indirect DNA damage, oxidative stress, inflammation, genomic instability, and interaction with hormonal regulation of the breast

Helm

Rudel

2020

Arch Toxicol

View full text Add to dashboard Cite

show abstract

“…Holtzman and colleagues showed no differences in mammary adenocarcinoma risk in a 10-month period after exposure in virgin, pregnant, lactating and postlactating Sprague–Dawley rats [68]. A similar-sized experiment but involving lifetime follow-up found comparably increased risk of radiation-associated mammary cancer for WAG/Rij rats exposed between ages 8 and 36 weeks, although none for rats exposed at the 'postmenopausal' age of 64 weeks [69]. …”

Section: Modification Of Dose Responsementioning

confidence: 99%

Radiation and breast cancer: a review of current evidence

2004

View full text Add to dashboard Cite

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.

show abstract

“…Firstly, the mice were irradiated at an earlier time of life (early puberty) compared to most women (who develop breast cancer at a median age ~60): In fact both for rodents [33] and humans [16,18], radiation-induced breast cancer risks fall off sharply for age at exposure in middle age. Younger mice were used in this validation study explicitly to enhance any potential radiation-induced carcinogenic effects: that the prophylactic effects at PMI doses dominated these carcinogenic effects even in a young mammary gland (where these carcinogenic effects are maximal) suggests that in older mammary glands the cancer risk reduction from PMI may be even more pronounced.…”

Section: Discussionmentioning

confidence: 99%

Potential Reduction of Contralateral Second Breast-Cancer Risks by Prophylactic Mammary Irradiation: Validation in a Breast-Cancer-Prone Mouse Model

et al. 2013

View full text Add to dashboard Cite

BackgroundLong-term breast-cancer survivors have a highly elevated risk (1 in 6 at 20 years) of contralateral second breast cancer. This high risk is associated with the presence of multiple pre-malignant cell clones in the contralateral breast at the time of primary breast cancer diagnosis. Mechanistic analyses suggest that a moderate dose of X-rays to the contralateral breast can kill these pre-malignant clones such that, at an appropriate Prophylactic Mammary Irradiation (PMI) dose, the long-term contralateral breast cancer risk in breast cancer survivors would be considerably decreased.AimsTo test the predicted relationship between PMI dose and cancer risk in mammary glands that have a high risk of developing malignancies. MethodsWe tested the PMI concept using MMTV-PyVT mammary-tumor-prone mice. Mammary glands on one side of each mouse were irradiated with X-rays, while those on the other side were shielded from radiation. The unshielded mammary glands received doses of 0, 4, 8, 12 and 16Gy in 4-Gy fractions. ResultsIn high-risk mammary glands exposed to radiation doses designed for PMI (12 and 16 Gy), tumor incidence rates were respectively decreased by a factor of 2.2 (95% CI, 1.1-5.0) at 12 Gy, and a factor of 3.1 (95% CI, 1.3-8.3) at 16 Gy, compared to those in the shielded glands that were exposed to very low radiation doses. The same pattern was seen for PMI-exposed mammary glands relative to zero-dose controls.ConclusionsThe pattern of cancer risk reduction by PMI was consistent with mechanistic predictions. Contralateral breast PMI may thus have promise as a spatially targeted breast-conserving option for reducing the current high risk of contralateral second breast cancers. For estrogen-receptor positive primary tumors, PMI might optimally be used concomitantly with systemically delivered chemopreventive drugs such as tamoxifen or aromatase inhibitors, while for estrogen-receptor negative tumors, PMI might be used alone.

show abstract

Induction of Mammary Tumors in Rats by Single-Dose Gamma Irradiation at Different Ages

Cited by 18 publications

References 25 publications

Adverse outcome pathways for ionizing radiation and breast cancer involve direct and indirect DNA damage, oxidative stress, inflammation, genomic instability, and interaction with hormonal regulation of the breast

Adverse outcome pathways for ionizing radiation and breast cancer involve direct and indirect DNA damage, oxidative stress, inflammation, genomic instability, and interaction with hormonal regulation of the breast

Radiation and breast cancer: a review of current evidence

Potential Reduction of Contralateral Second Breast-Cancer Risks by Prophylactic Mammary Irradiation: Validation in a Breast-Cancer-Prone Mouse Model

Contact Info

Product

Resources

About