RERF Report No. 3-15

A research paper published in the International Journal of Radiation Biology“Bioavailable serum estradiol may alter radiation risk of postmenopausal breast cancer:
a nested case-control study”
Eric J. Grant, John B Cologne, Gerald B. Sharp, Hidetaka Eguchi, Richard G. Stevens, Shizue Izumi,
Young-Min Kim, Amy Berrington de González, Waka Ohishi and Kei Nakachi
Int J Radiat Biol. 2018;9(3):1–27.
(doi: 10.1080/09553002.2018.1419303)
Study Findings
Results showed modest evidence that radiation exposure increased the risk of breast cancer
through a biological system not typically considered: an indirect pathway in which circulating
estradiol levels were raised after radiation exposure. Higher levels of estradiol (an estrogen) have long
been known to be associated with higher breast cancer rates. A unique feature of this study was theability to investigate serum estrogen levels that had been collected prior to breast cancer diagnosis.
Biological measurements made before disease onset are more reliable for research purposes, providing
justification for our conclusions despite the small size of the study. Nevertheless, further work isneeded to clarify and increase confidence in the findings.
Explanation
Ionizing radiation exposure and estradiol (the predominant estrogen in women) are both known
breast carcinogens. It has been understood for some time that radiation exposure can lead to breast
cancer through direct mutations induced in breast tissue, but little is known about the role of radiationin relation to endogenous sex hormones. In a recent study, we observed that radiation exposure wasassociated with higher levels of estradiol in women who did not suffer breast cancer. We therefore
wondered if radiation exposure might have increased the risk of breast cancer by increasing estradiollevels. This is called a mediated path and is shown as the dotted line in the Figure below. We
evaluated the level of mediation and determined that a small but statistically significant fraction of theoverall radiation risk was through this pathway.

Figure. Radiation exposure increases the risk of breast cancer. Higher serum estradiol concentration is also a known breast
carcinogen. In a previous study, we observed that radiation exposure caused an increase in estradiol level (dotted line). We
can test how much of the radiation risk of breast cancer is by the direct path versus an indirect path (i.e. through raisingestradiol levels which, in turn, raises breast cancer risks) through a statistical test for “mediation.”

1. Study purpose
A previous, interview-based study of female atomic bomb survivors in the RERF Life Span
Study produced evidence of interaction between radiation and reproductive behaviors. Generally,protective factors (such as earlier age at first pregnancy and more children) also lowered the risks ofcancer after radiation exposure. However, the mechanism for such an interaction was not clear,although there was reason to speculate that it might involve cumulative exposure to endogenous sex
hormones such as estradiol. We therefore investigated the risk of breast cancer in relation to the
combined effects of whole-body ionizing radiation exposure and prediagnostic levels of1

RERF Report No. 3-15

postmenopausal sex hormones, particularly bioavailable estradiol (bE 2 ), with two aims: one was toassess whether a similar interaction exists between radiation dose and endogenous sex hormone levels,and the other was to assess the potential role of mediation (as explained above). Because the survivors
were at older ages at the time the study was conducted, we focused on post-menopausal breast cancer,
which comprised the majority of cases.
2. Study methods
We investigated the risks of breast cancer by using a nested case-control study of 57 incident
breast cancer cases matched with 110 controls among atomic bomb survivors who attended the RERF
clinic as part of the Adult Health Study. Risk factors for breast cancer that were investigated in thisstudy included radiation dose to the breast, levels of various serum hormones, age at menarche, age atmenopause, body mass index, and several factors related to parity. Joint effects of breast radiationdose and circulating levels of sex hormones were assessed using binary regression and path analysis.
3. Study results
Findings related to breast cancer in general were as expected, in that breast cancer risk wasassociated with known risk factors, including higher radiation doses, higher levels of endogenous sex
hormones (bE 2 , testosterone, and progesterone), and higher body mass index levels. Also, breast
cancer risks were lower in women with later onset of menarche and a greater number of pregnancies,
which are factors known to reduce the risk of breast cancer. Analyses of interaction between radiationand serum hormones were inconclusive. A test for mediation of the effect of radiation via bE 2 level
suggested a small (14%) but significant mediation (p=0.002). The interpretation of this is that about
14% of the total radiation risk, or occurrence of excess cases of cancer among radiation-exposedwomen, might be the result of higher estradiol levels induced by the radiation exposure as opposed toother mechanisms including direct mutations in breast tissue induced by radiation.
Study Significance
There is accumulating evidence that ionizing radiation not only damages DNA (a primary causeof cancer), but also induces alterations in other organ systems, which can further increase the risk ofcancer. The results suggest that some portion of the radiation risk of postmenopausal breast cancer
might be mediated through bE 2 levels. If this can be confirmed, it would suggest a previously
unknown mechanism of radiation risk that could be used for intervention to reduce risk for radiation
exposure.
The Adult Health Study cohort is one of the few resources in the world with which a study ofthis nature could be performed. Unique features include the existence of stored biological specimensthat predate the onset of disease and the collection of data in a controlled clinical setting. Based onsuch advantages, the effects of radiation can be studied in terms of both its direct effects and its effecton systemic changes that can be measured in the clinic.
The study was quite small with only 57 cases, and therefore, while the results were interesting
and raise important questions on the mechanisms of radiation-associated breast cancer, the results
should be interpreted cautiously, because small studies can sometimes produce ambiguous or nonrepeatable results.
The Radiation Effects Research Foundation has studied A-bomb survivors and their offspring in Hiroshimaand Nagasaki for around 70 years. RERF’s research achievements are considered the principal scientific basis
for radiation risk assessment by the United Nations Scientific Committee on the Effects of Atomic Radiation(UNSCEAR) and for recommendations regarding radiation protection standards by the International
Commission on Radiological Protection (ICRP). RERF expresses its profound gratitude to the A-bomb survivors
and survivors’ offspring for their cooperation in our studies.
International Journal of Radiation Biology is a monthly peer-reviewed medical journal that covers research inthe field of biology on the effects of ionizing and non-ionizing radiation. (Impact factor in 2016/2017: 1.992)

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