MIRAMARE

Mechanisms of the inversed relationship between menarche age and radiation-induced breast and endometrial cancer

Project objectives and goals

The risk of radiogenic breast and endometrial cancer is highest following exposure around puberty. This is explained by the developing breast and endometrial tissue, driven by oestrogen. However, what is puzzling is that age at menarche (the first menstrual period) is a strong modifier of risk irrespective of the age at exposure: for any age at exposure the relative risk of radiation-induced breast and endometrial cancer is highest for women who had menarche at an early age. The increase of risk with decreasing menarche age is, on average, 24% for breast cancer and 31% for endometrial cancer per year of decreasing menarche age. The mechanisms are not understood but one factor responsible for early menarche age is obesity. It is possible that the inversed correlation between menarche age and cancer results from the interaction of obesity-related factors, sex hormones and radiation.
The overall aim of MIRAMARE is to gain a mechanistic understanding of the inversed relationship between menarche age and susceptibility to radiogenic breast and endometrial cancer. MIRAMARE will test the hypothesis that obesity is a major factor that decreases the menarche age, by analysing various hallmarks of cancer in cells treated under in vitro conditions to acute and chronic radiation in combination with the obesity hormone leptin and sex hormones estrogen and progesteron. The targeted breakthroughs are: 1) mechanistic understanding of the interaction of obesity with radiation; 2) mechanistic understanding of the interaction of sex hormones with radiation; 3) mechanistic understanding of the inversed relationship between menarche age caused by obesity and cancer risk; 4) new knowledge on the mechanisms and occurrence of an inversed relationship between menarche age and susceptibility to radiogenic breast and endometrial cancer in response to chronic exposure to radiation.

Overall structure of the work plan

The hypothesis of MIRAMARE is that the inversed relationship between menarche age and susceptibility to radiogenic breast and endometrial cancer results from the interaction of obesity-related factors with sex hormones and radiation. To test this hypothesis breast and endometrial cell lines will be used as the breast and endometrium cell models. The impact of obesity alone will be studied by pre-treating irradiated cells with the obesity hormone leptin (intermediate target 1). The impact of sex hormones alone will be studied by pre-treating irradiated cells with oestrogen and progesterone (intermediate target 2). Various combinations of the hormones and radiation will be tested to see how they interact (final target). Cells will be exposed to radiation acutely and chronically to improve risk assessment following low dose rate exposure (intermediate target 3). Analyses will include cancer-related changes at the level of the epigenome and genome (WP2), immune parameters (WP3), and stem cell-ness and senescence (WP4). WP5 on biostatistics will ensure proper data integration and exploitation. The workplan is shown in the PERT diagram and the scheme. MIRAMARE will organize a course in which the interaction of life-style factors and radiation on cancer risk will be taught. Also, we will organise interventions at secondary schools on the possibilities of prevention of spontaneous and radiogenic cancers by modifying lifestyle factors such as nutrition. Students´ reasoning and arguments will be recorded and analysed. Results will serve as basis for future teaching curricula.



PERT diagram

Project coordinator

Andrzej Wojcik, Centre for Radiation Protection Research, MBW Department, Stockholm University, Sweden

Deliverables

D9.113	MIRAMARE - D1.1 Quality assurance plan and project management handbook	R - Document, report
D9.126	MIRAMARE - D5.1 Data Management Plan	DMP - Data management plan