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Contribution of development and age to breast cancer etiology

发育和年龄对乳腺癌病因的贡献

基本信息

批准号：
8972933
负责人：
Mary Helen Barcellos-Hoff
金额：
$ 3.02万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8972933
关键词：
Address Adult Affect Age Age-Years American BRCA1 gene Bioinformatics Biological Biological Assay Breast Carcinoma Cancer Etiology Cells Child Childhood Chimera organism Chronic Collaborations Colon Contralateral DNA Damage Dependence Development Diagnostic Dose ERBB2 gene Epidemiologic Studies Epithelium Fatty acid glycerol esters Flow Cytometry Frequencies Gene Mutation General Population Genes Germ-Line Mutation Hormone Receptor Human Incidence Inflammation Ionizing radiation Life Link Literature Lung Malignant - descriptor Malignant Childhood Neoplasm Malignant Neoplasms Mammary Tumorigenesis Mammary gland Mediating Medical Menopause Modeling Mus Mutation North Carolina Obesity Perinatal Exposure Phenotype Predisposition Prevention Process Puberty Publishing Quantitative Microscopy Radiation Radiation Genetics Radiation therapy Rattus Relative Risks Risk Risk Factors Route Second Primary Cancers Shapes Specimen Stem cells Testing Therapeutic Thyroid Gland Tissues Transforming Growth Factor beta Transplantation United States Universities Weaning Woman base cancer genomics cancer risk carcinogenesis case control childhood cancer survivor cohort girls in utero irradiation macrophage malignant breast neoplasm mammary epithelium miRNA expression profiling novel prevent prophylactic public health relevance radiation carcinogenesis radiation effect radiation response research study self-renewal tissue processing triple-negative invasive breast carcinoma tumor

项目摘要

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.

描述（由申请人提供）：据估计，在美国，1/10的第二原发性癌症是由于第一癌症的放射治疗。特别令人关注的是那些已经成功治疗癌症的儿童。与未接受放射治疗的女孩相比，接受放射治疗的女孩随后患乳腺癌的相对风险为2.9，与BRCA 1生殖系突变相当。此外，最近的研究特别将儿童放射治疗与早期乳腺癌的发展联系起来，早期乳腺癌的特征是侵袭性和三阴性乳腺癌（TNBC），对激素受体和HER 2扩增呈阴性。相反，接受乳腺癌放疗的成年女性患对侧乳腺癌的相对风险为1.2。这些研究和其他流行病学研究表明，辐射风险与受照射年龄成反比;青春期受照射风险最大，而绝经期后受照射风险似乎很低。然而，由于观察到子宫内的辐射照射几乎不会增加患癌症的风险，年龄依赖性进一步复杂化。放射性癌症通常仅通过细胞内在效应的棱镜来考虑，即DNA损伤和对偶尔引发转化的突变的易感性，但这种范式不能解释子宫内暴露的影响缺乏或辐射前乳腺癌中TNBC的高发生率。根据我们发表的和初步的研究，我们提出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增，而后者与侵袭性乳腺癌的发展相关。我们假设，青春期辐射暴露的强敏感性窗口是由于对乳腺干细胞和巨噬细胞的影响，它们共同创造了促进恶性进展的关键环境。在这里，我们将测试辐射诱导的TGF β 1连接这两个过程的假设。我们的研究将解决以下目标：1。辐射前的人类乳腺癌与散发性乳腺癌有区别吗？2. TGF β 1在辐射暴露时是否作为年龄的函数差异性地改变干细胞池和巨噬细胞表型？3.辐射暴露作为年龄的函数会促进小鼠的侵袭性肿瘤吗？了解这种年龄依赖性有可能重新塑造目前的致癌模式，重点关注组织过程，也可以提供预防途径。