Contribution of development and age to breast cancer etiology

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 DESCRIPTION (provided by applicant): It is estimated that 1/10 second primary cancers in the United States are due to radiotherapy for first cancers. Of particular concern are children who have been successfully treated for cancer. In comparison to girls who did not receive radiotherapy, girls treated for cancer with radiotherapy have a 2.9 relative risk of subsequently developing breast cancer, which is comparable to BRCA1 germ line mutation. Moreover, recent studies specifically associate childhood radiation treatment with the development of early that is characterized as aggressive and triple-negative breast cancer (TNBC) negative for hormone receptors and HER2 amplification). In contrast, the relative risk for contralateral breast cancer i 1.2 in adult women treated with radiation for breast cancer for. These and other epidemiological studies show that radiation risk and age at exposure are inversely related; exposure during puberty poses the greatest risk while exposures past the menopause appear to carry very low risk. However, age dependence is further complicated by the observation that radiation exposure in utero confers little increased risk for cancer. Radiogenic cancer is often considered exclusively through the prism of cell intrinsic effects, i.e. DNA damage and susceptibility to mutations that occasionally initiate transformation, but this paradigm cannot explain the lack of effect of in utero exposure or the high rate of TNBC in radiation-preceded breast cancer. Based on our published and preliminary studies, we propose that tissue responses to radiation determine this aspect of cancer risk. Our mouse experiments show that radiation exposure during puberty induces inflammation and stem cell expansion, and that the latter correlates with development of aggressive mammary carcinomas. We hypothesize that the strong susceptibility window for radiation exposure during puberty is due to effects on mammary stem cells and macrophages, which together create the critical context to promote malignant progression. Here, we will test the hypothesis that radiation-induced TGFß links these two processes. Our studies will address the following aims: 1. Are radiation-preceded human breast cancers distinct from sporadic breast cancers? 2. Does TGFß differentially alter stem cell pool and macrophage phenotype as a function of age at radiation exposure? 3. Does radiation exposure as a function of age promote aggressive tumors in mice? Understanding this age dependence has the potential to re-shape the current carcinogenesis paradigm to focus on tissue processes that could also provide routes to prevention.