Smoking as a Proxy for Nicotine Exposure and Risk of EGFR Positive Breast Cancer

吸烟可作为尼古丁暴露和 EGFR 阳性乳腺癌风险的替代指标

• 批准号: 8986887
• 负责人: Ebonee Nicole Butler
• 金额: $ 3.4万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2017-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8986887
• 关键词: African American; Age; Behavior; Biological Markers; Blood; Blood specimen; Breast; Breast Cancer Patient; Breast Cancer Risk Factor; Breast Carcinogenesis; Cancer Etiology; Cell Proliferation; Chemicals; Cigarette; Complex Mixtures; DNA; DNA Adducts; Data; Detection; Diagnosis; EGFR Protein Overexpression; Environment; Environmental Exposure; Epidemiologic Methods; Epidemiologic Studies; Epidemiology; Epidermal Growth Factor Receptor; Epithelium; Etiology; Fellowship; Foundations; Genes; Genetic; Genetic Variation; Genotype; Heterogeneity; Human; In Vitro; Individual; Investigation; Link; Mammary Gland Parenchyma; Mammary Neoplasms; Masks; Measurable; Mediating; Molecular; Nicotine; Nicotinic Receptors; Pathology; Patient Self-Report; Patients; Pattern; Play; Population Study; Predisposition; Prognostic Marker; Proxy; Recurrence; Research Personnel; Research Training; Resources; Risk; Risk Factors; Risk Reduction; Role; Saliva; Sampling; Single Nucleotide Polymorphism; Smoker; Smoking; Smoking History; Smoking Status; Staining method; Stains; Testing; Time; To specify; Tumor Subtype; United States; Variant; Woman; base; bead chip; cancer risk; carcinogenesis; case control; cell motility; environmental agent; genetic variant; human tissue; in vivo; innovation; insight; malignant breast neoplasm; modifiable risk; mortality; neoplastic cell; novel; overexpression; prognostic value; protein function; public health relevance; receptor expression; risk variant; smoking cessation; targeted treatment; theories; tumor

 DESCRIPTION (provided by applicant): In 2014, an estimated 232,000 women in the United States will be diagnosed with breast cancer. Three- fourths will have no known heritable susceptibility, suggesting that environments and individual behaviors play a substantial role in breast carcinogenesis. The existence of breast cancer intrinsic subtypes adds to the difficult task of understanding breast cancer etiology, as each subtype is hypothesized to have a distinct risk factor profile. In addition, aggressive subtypes are important focal points for risk factor identification and risk reduction strategies since these tumors often do not benefit from available targeted therapies and are associated with higher mortalities. Researchers have proposed smoking as a probable risk factor for breast cancer based on epidemiologic findings and the detection of nicotine and cigarette byproducts (e.g., DNA adducts) in breast tissues of smokers. Contemporary in vitro studies of breast epithelium treated with nicotine have demonstrated increased rates of cell proliferation through over activation of the epidermal growth factor receptor (EGFR), thereby establishing a measurable biologic endpoint to test the hypothesis that smoking - and concomitant nicotine exposure - is associated with EGFR positive (EGFR+) breast cancer. Defined by immunohistochemical staining in greater than ten percent of examined tumor cells, EGFR-positivity is a poor prognostic marker and is most common among African American (AA) patients. In vitro studies have also shown that nicotine-induced breast carcinogenesis is mediated by the a-9 subunit of the nicotinic acetylcholine receptor (nAChR). Moreover, if nAChR mediates smoking-related breast carcinogenesis in vivo, it is conceivable that smoking interaction with genetic variants of the nAChR a-9 subunit may be associated with differential risk of EGFR+ breast cancer. This research training plan and novel study resource will allow the fellowship applicant to establish a foundation in theories of carcinogenesis and gain expertise in molecular epidemiologic methods needed to examine the hypothesis that nicotine exposure confers an increased risk of EGFR+ breast cancer. Aim 1: Using smoking status as a proxy for nicotine exposure in vivo, we will examine the relationship between smoking and EGFR+ breast cancer. We will use parametric latency functions to identify time frames during a woman's lifetime where smoking is associated with the greatest risk of EGFR+ breast cancer. Aim 2: We will also examine whether smoking interaction with common variants of the nAChR a-9 subunit confers differential risk of EGFR+ breast cancer; this interaction will be assessed using single nucleotide polymorphisms of its encoding gene, CHRNA9, as surrogates for variations in protein function. The AMBER project is a consortium of four studies of AA women, including 5,739 breast cancer cases and 14,273 controls with self-reported data on environmental exposures, DNA obtained from saliva or blood specimens, and tumor samples. This consortium provides an idea study population to examine the etiology of EGFR+ breast cancer since EGFR-positivity is most common among AA patients.

 描述（由申请人提供）：2014年，美国估计有232，000名女性将被诊断患有乳腺癌。四分之三的人没有已知的遗传易感性，这表明环境和个人行为在乳腺癌发生中起着重要作用。乳腺癌内在亚型的存在增加了理解乳腺癌病因的困难任务，因为假设每个亚型具有不同的风险因素特征。此外，侵袭性亚型是风险因素识别和风险降低策略的重要焦点，因为这些肿瘤通常不能从现有的治疗中获益。 靶向治疗，并与较高的死亡率相关。研究人员提出吸烟是乳腺癌的一个可能的危险因素，这是基于流行病学调查结果和尼古丁和香烟副产物的检测（例如，DNA加合物）。对尼古丁处理的乳腺上皮进行的当代体外研究表明，通过过度激活表皮生长因子受体（EGFR），细胞增殖率增加，从而建立了可测量的生物学终点，以检验吸烟和伴随的尼古丁暴露与EGFR阳性（EGFR+）乳腺癌相关的假设。通过免疫组织化学染色确定超过10%的检查肿瘤细胞，EGFR阳性是一种预后不良的标志物，在非洲裔美国人（AA）患者中最常见。体外研究还表明，尼古丁诱导的乳腺癌发生是由烟碱乙酰胆碱受体（nAChR）的a-9亚基介导的。此外，如果nAChR介导体内吸烟相关的乳腺癌发生，那么可以想象，吸烟与nAChR a-9亚基的遗传变异的相互作用可能与EGFR+乳腺癌的不同风险相关。这项研究培训计划和新的研究资源将使奖学金申请人建立致癌理论的基础，并获得研究尼古丁暴露会增加EGFR+乳腺癌风险的假设所需的分子流行病学方法的专业知识。目的1：使用吸烟状态作为体内尼古丁暴露的代表，我们将研究吸烟与EGFR+乳腺癌之间的关系。我们将使用参数潜伏期函数来确定女性一生中吸烟与EGFR+乳腺癌最大风险相关的时间范围。目标二：我们还将研究吸烟与nAChR a-9亚基常见变异的相互作用是否赋予EGFR+乳腺癌的差异风险;将使用其编码基因CHRNA 9的单核苷酸多态性作为蛋白质功能变异的替代物来评估这种相互作用。AMBER项目是一个由四项AA女性研究组成的联盟，其中包括5，739例乳腺癌病例和14，273例对照组，这些病例和对照组自我报告了环境暴露数据，从唾液或血液标本中获得的DNA以及肿瘤样本。该联盟提供了一个理想的研究人群，以检查EGFR+乳腺癌的病因，因为EGFR阳性在AA患者中最常见。