Contribution of development and age to breast cancer etiology

 描述(申请人提供)：据估计，在美国，十分之一的第二原发癌是由于第一癌症的放射治疗。特别令人担忧的是那些成功治疗癌症的儿童。与没有接受放射治疗的女孩相比，接受放射治疗的女孩患乳腺癌的相对风险为2.9，这与BRCA1生殖系突变相当。此外，最近的研究明确地将儿童时期的放射治疗与早期乳腺癌的发展联系起来(表现为侵袭性和三阴性乳腺癌(TNBC)，激素受体和HER2扩增阴性)。相比之下，接受乳腺癌放射治疗的成年女性患对侧乳腺癌的相对风险为1.2。这些和其他流行病学研究表明，辐射风险与暴露年龄成反比；青春期的暴露风险最大，而绝经后的暴露风险似乎很低。然而，由于观察到宫内辐射暴露几乎不会增加患癌症的风险，年龄相关性变得更加复杂。放射致癌通常被认为完全是通过细胞内在效应的棱镜来考虑的，即DNA损伤和对偶尔启动转化的突变的易感性，但这种范式不能解释宫内暴露的影响或辐射前乳腺癌中TNBC的高比率。基于我们已发表的和初步的研究，我们认为组织对辐射的反应决定了癌症风险的这一方面。我们的小鼠实验表明，青春期的辐射暴露会诱导炎症和干细胞扩张，而后者与侵袭性乳腺癌的发生有关。我们假设，青春期辐射暴露的强烈敏感性窗口是由于对乳腺干细胞和巨噬细胞的影响，这两种细胞共同创造了促进恶性进展的关键背景。在这里，我们将检验辐射诱导的转化生长因子将这两个过程联系在一起的假设。我们的研究将致力于以下目标：1.接受放射治疗的人类乳腺癌与散发性乳腺癌有区别吗？2.在辐射暴露时，转化生长因子是否会改变干细胞池和巨噬细胞的表型，作为年龄的函数？3.辐射暴露是否会促进小鼠侵袭性肿瘤的发生？了解这种年龄依赖性有可能重塑当前的癌症发生范式，将重点放在组织过程上，这也可能提供预防途径。

 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.