Variation in Receptor Tyrosine Kinases and Breast Cancer Risk

受体酪氨酸激酶变异与乳腺癌风险 很明显，患乳腺癌的部分风险是由基因决定的。基因的贡献 乳腺癌风险可能来自人群中常见或罕见的变异（或两者兼而有之）。为了 系统地评估常见和罕见的多态性，我们建议应用一个结构化和高度 多学科双管齐下的方法，旨在最初最大限度地提高检测每个影响的能力 乳腺癌风险的一类变异。对于常见变异，我们将重点关注癌症关联研究 使用来自护士健康研究中乳腺癌病例和对照组的DNA， SPORE的高风险队列。更罕见的错义变体将受到功能性细胞和 分子检测，结合追踪家族性乳腺癌病例中的变异。任何变体， 将通过补充方法追求正分数（对于功能或关联）。上一 为了从孢子周期中识别基因，我们采用了乳腺腺泡的三维（3D）培养模型， “乳腺癌1000”cDNA文库诱导类似乳腺癌相关事件的表型变化 肿瘤的发生和发展。在这些结果的基础上，我们将首先关注四种候选受体， 酪氨酸激酶，表现出最显着的表型效应：EGF-R，CSF-1 R，ERBB 2，和IGF-1。 1 R.这种研究方法将在未来几年扩展到其他基因。在这份提案中，我们将 具体而言：1）测试在一系列风险类别中与乳腺癌相关的常见变异，2） 检测罕见变异体的可区分功能活性以及与家族性和早发性乳腺癌的相关性 3）研究遗传变异与乳腺癌受体表达状态之间的关系， 散发性乳腺癌和4）当可能时，评估这些循环配体的相关性 受体和随后的乳腺癌风险。使用这种范式来研究遗传变异的作用 和乳腺癌之间的关系，我们希望能够确定与乳腺癌风险相关的适度渗透等位基因。

VARIATION IN RECPTOR TYROSINE KINASES AND BREAST CANCER RISK It is clear that part of the risk of developing breast cancer is genetically determined. The genetic contribution to breast cancer risk may arise from either common or rare variants (or both) in the population. In order to systematically assess both common and rare polymorphisms, we propose to apply a structured and highly multidisciplinary two pronged approach designed to initially maximize the power to detect the effect of each class of variants on breast cancer risk. For the common variants, we will focus on cancer association studies using DNA from breast cancer cases and controls in the Nurses' Health Study and breast cancer cases from the SPORE's High Risk Cohort. The rarer missense variants will be subjected to functional cellular and molecular assays, combined with tracking of the variants in cases of familial breast cancer. Any variant that scores positive (for function or association) will be pursued by the complementary approach. In the previous SPORE cycle, we employed a 3-dimensional (3D) culture model of breast acini to identify genes from the 'Breast Cancer 1000' cDNA library that induce phenotypic changes resembling events associated with breast tumor initiation and progression. Building on these results, we will initially focus on four candidate receptor tyrosine kinases, which showed the most dramatic phenotypic effects: EGF-R, CSF-1R, ERBB2, anc IGF- 1R. This research approach will be extended to other genes in future years. In this proposal, we wilt specifically: 1) test common variants for association with breast cancer across a spectrum of risk classes, 2) test rare variants for distinguishable functional activity and association with familial and early-onset breast cancer, 3) examine the relationship between genetic variation and breast tumor receptor expression status in sporadic breast cancer and 4) when possible evaluate the association of circulating ligands for these receptors and subsequent breast cancer risk. Using this paradigm to investigate the role of genetic variation and breast cancer, we hope to identify modestly penetrant alleles conferring breast cancer risk.