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: 9145079
• 负责人: Ebonee Nicole Butler
• 金额: $ 3.44万
• 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/9145079
• 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; 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; 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; mammary epithelium; modifiable risk; mortality; neoplastic cell; novel; overexpression; prognostic value; protein function; public health relevance; receptor expression; risk variant; smoking cessation; study population; 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，估计美国将有 232,000 名女性被诊断患有乳腺癌。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了解乳腺癌病因学的艰巨任务，因为假设每种亚型都具有独特的危险因素特征。此外，侵袭性亚型是危险因素识别和风险降低策略的重要焦点，因为这些肿瘤通常无法从现有的治疗中受益。 靶向治疗并与较高的死亡率相关。研究人员根据流行病学发现以及吸烟者乳腺组织中尼古丁和香烟副产品（例如 DNA 加合物）的检测，提出吸烟是乳腺癌的一个可能危险因素。当代对用尼古丁处理的乳腺上皮进行的体外研究表明，通过表皮生长因子受体（EGFR）的过度激活，细胞增殖率增加，从而建立了一个可测量的生物学终点来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。 EGFR 阳性是通过对超过 10% 的检查肿瘤细胞进行免疫组织化学染色来定义的，EGFR 阳性是一个不良的预后标志物，并且在非裔美国人 (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 在体内介导与吸烟相关的乳腺癌发生，那么可以想象，吸烟与 nAChR a-9 亚基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颖的研究资源将使奖学金申请人能够建立致癌理论基础，并获得分子流行病学方法方面的专业知识，以检验尼古丁暴露会增加 EGFR+ 乳腺癌风险的假设。目标 1：使用吸烟状况作为体内尼古丁暴露的指标，我们将研究吸烟与 EGFR+ 乳腺癌之间的关系。我们将使用参数延迟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 2：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会导致 EGFR+ 乳腺癌的不同风险；这种相互作用将使用其编码基因 CHRNA9 的单核苷酸多态性作为蛋白质功能变化的替代物进行评估。 AMBER 项目是由四项针对 AA 女性的研究组成的联盟，其中包括 5,739 例乳腺癌病例和 14,273 例对照者，并提供有关环境暴露、从唾液或血液样本中获取的 DNA 以及肿瘤样本的自我报告数据。该联盟提供了一个理想的研究人群来检查 EGFR+ 乳腺癌的病因，因为 EGFR 阳性在 AA 患者中最常见。