Bioavailable serum estradiol may alter radiation risk of postmenopausal breast cancer: a nested case-control study

Abstract

Purpose: Ionizing radiation and high levels of circulating estradiol are known breast cancer carcinogens. We investigated the risk of first primary postmenopausal breast cancer in relation to the combined effects of whole-body ionizing radiation exposure and prediagnostic levels of postmenopausal sex hormones, particularly bioavailable estradiol (bE₂).

Materials and methods: A nested case-control study of 57 incident breast cancer cases matched with 110 controls among atomic bomb survivors. Joint effects of breast radiation dose and circulating levels of sex hormones were assessed using binary regression and path analysis.

Results and conclusion: Radiation exposure, higher levels of bE₂, testosterone and progesterone, and established reproductive risk factors were positively associated with postmenopausal breast cancer risk. A test for mediation of the effect of radiation via bE₂ level suggested a small (14%) but significant mediation (p = 0.004). The estimated interaction between radiation and bE₂ was large but not significant (interaction = 3.86; p = 0.32). There is accumulating evidence that ionizing radiation not only damages DNA but also alters other organ systems. While caution is needed, some portion of the radiation risk of postmenopausal breast cancer appeared to be mediated through bE₂ levels, which may be evidence for cancer risks due to both direct and indirect effects of radiation.

Keywords:

• Breast cancer
• hormones
• estradiol
• radiation
• postmenopausal
• interaction
• mediation

Acknowledgements

We thank the women of the AHS study for graciously donating biosamples. We also thank Dr. Roy Shore for his many helpful comments and suggestions, and Dr. Kazuo Neriishi for his assistance and advice.

Disclosure statement

No potential conflict of interest was reported by the authors.

Notes on contributors

Eric J. Grant received his PhD in Epidemiology from the University of Washington in Seattle and has worked at RERF for many years with an interest in modeling and solid cancer risks from radiation exposure. He is now the Associate Chief of Research at RERF.

John B. Cologne, PhD, is Senior Research Scientist, Department of Statistics, Radiation Effects Research Foundation. He has co-authored many papers describing analyses of cancer risk among the Atomic-bomb Survivors, especially in regards to breast and liver cancer. His primary interests are efficient epidemiologic study design and mediation in causal mechanisms.

Dr. Gerald B. Sharp received his DrPH degree in Cancer epidemiology from UAB and joined RERF in 1997 where he primarily studied effects of radiation and HCV on liver cancer etiology. He joined NIAID in 2003 and is a project scientist for large cohort studies studying HIV in the USA and Asia.

Hidetaka Eguchi is Associate Professor of Diagnostics and Therapeutics of Intractable Diseases, Graduate School of Medicine, Juntendo University, and Part-time Lecturer at the Research Center for Genomic Medicine, Saitama Medical University. He is also an Editorial Board Member of the journal Carcinogenesis.

Richard G. Stevens received a B.S. in Genetics from UC Berkeley, and a Ph.D. in Epidemiology from the University of Washington. His recent research has focused on the potential role of lighting and circadian disruptions leading to increased risk of breast cancer, an idea currently receiving scientific and public interest.

Shizue Izumi has been a professor of the Center for Data Science Education and Research, Shiga University, Japan since April 1, 2016. She was previously a research scientist in the department of Statistics, Radiation Effects Research Foundation until 2004. Her interests include statistics in general, statistical education, and molecular epidemiology.

Young-Min Kim, Ph.D., is an assistant professor, Department of Statistics, College of Natural Science, Kyungpook National University. He previously served as a research scientist of the Department of Statistics, Radiation Effects Research Foundation, Hiroshima, Japan. His interests include causal mediation, radiation-associated risks, bootstrap, and empirical likelihood methods.

Dr. Amy Berrington de González received a D.Phil. in Cancer Epidemiology from the University of Oxford and is currently the Chief of the Radiation Epidemiology Branch at NCI. She has served on radiation risk committees for the National Academy of Science, the UK Health Protection Agency, and UK Breast Screening Programme.

Waka Ohishi, MD, PhD, is Chief, Department of Clinical Studies, Hiroshima, Radiation Effects Research Foundation. She is a hepatologist and councilor for the Japanese Society of Gastroenterology. Her interests are radiation effects on cancer and non-cancer disease among atomic-bomb survivors, especially liver cancer risk.

Kei Nakachi, PhD, is the former Chief, Department of Radiobiology and Molecular Epidemiology, RERF. He is Emeritus Fellow of the American Association for Cancer Research, the Japanese Cancer Association, and the Japanese Society of Cancer Epidemiology. Dr. Nakachi has published more than 200 peer-reviewed papers primarily on cancer molecular epidemiology.

Additional information

Funding

The Radiation Effects Research Foundation (RERF), Hiroshima and Nagasaki, Japan is a public interest foundation funded by the Japanese Ministry of Health, Labour and Welfare and the US Department of Energy (DOE). The research was also funded in part through DOE award DE-HS0000031 to the National Academy of Sciences, US National Cancer Institute contracts HHSN261200900005C and HHSN261201400009C, and the Japanese Ministry of Education, Culture, Sports, Science and Technology grants 14031227, 15026220, and 17K00047 (S. Izumi). The views of the authors do not necessarily reflect those of the two funding governments.