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，有 1/10 的第二原发性癌症是由原发性癌症的放射治疗引起的，与未接受癌症治疗的女孩相比，特别值得关注的是已接受癌症治疗的儿童。接受放射治疗的女孩随后患乳腺癌的相对风险为 2.9，这与 BRCA1 种系突变相当。此外，最近的研究特别将儿童放射治疗与具有侵袭性和侵袭性的早期乳腺癌的发展联系起来。激素受体和 HER2 扩增呈阴性的三阴性乳腺癌 (TNBC) 相比之下，接受放射治疗的成年女性患乳腺癌的相对风险 i 1.2 这些和其他流行病学研究表明，放射风险和暴露时的年龄呈负相关；青春期期间的暴露风险最大，而绝经期后的暴露风险似乎非常低。然而，由于观察到子宫内的辐射暴露几乎没有什么风险，因此年龄依赖性变得更加复杂。放射源性癌症的风险增加通常是通过细胞固有的影响来考虑的，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的缺乏或TNBC的高发生率。根据我们已发表的初步研究，我们提出，组织对辐射的反应决定了癌症风险的这一方面。和我们认为青春期辐射暴露的强易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，我们将检验辐射的假设。诱导的 TGFβ 将这两个过程联系起来。我们的研究将致力于以下目标：1. 放射治疗前的人类乳腺癌是否与散发性乳腺癌不同？ 2. TGFβ 是否会差异性地改变干细胞池？ 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塑当前的致癌范式，以关注可能的组织过程。还提供预防途径。