Breast Cancer Risk: Analysis of heightened HPA axis stress responsivity

描述(申请人提供)：对于美国每年20多万名确诊为乳腺癌的妇女的健康女儿和姐妹来说，这种疾病的威胁尤为突出。从生物学上讲，他们携带的基因会增加他们患乳腺癌的可能性。即使在考虑了BRCA1/2之后，在其家族中患有乳腺癌的妇女(FH+)的人口风险至少是BRCA1/2的两倍。在心理上，他们有焦虑、抑郁和创伤后应激症状的风险，即使在确诊数年后也是如此。一种未被研究的可能性是，这些女性可能对急性应激也有下丘脑-垂体-肾上腺(HPA)轴(如皮质醇)反应增强，这是应激影响健康的主要途径。遗传和/或心理因素对这种高响应性的贡献尚未得到调查。这项拟议研究的总体目标是检验这样一种假设，即有乳腺癌家族史的健康女性HPA轴应激反应增强，并调查家族史的遗传和心理方面对反应变异性的贡献。将招募健康的、FH+的、绝经前的、工作的妇女和频率匹配的FH样本。经过严格的预筛选以减少外部的变异性来源，HPA轴的压力响应性将在两个公认的、严格控制的压力范例中进行评估：1)实验室方法，Trier社会压力测试(高内部效度)；2)“现实世界”方法，日常生活中的工作压力-压力(高外部效度)。这些方法的综合结果将被统计检验(n=220，具有完整的数据)，以探索家庭历史对压力反应的影响的更广泛的模型。本研究的研究目的是：1)研究乳腺癌家族史与受控实验室条件下女性HPA轴应激反应的关系；2)研究乳腺癌家族史与自然条件下女性皮质醇应激反应的关系；3)采用结构方程分析方法，评价乳腺癌家族史和乳腺癌家族史心理后遗症对实验室和自然条件下女性皮质醇应激反应的影响。公共卫生相关性：如果拟议的研究结果表明，家族史的遗传方面对HPA轴对压力的敏感度提高有重大贡献，这将增加这些女性对应激反应的遗传易感性可能是导致她们患乳腺癌风险增加的机制的可能性，并将为这种疾病的病因开辟一个新的研究领域，每年有20多万美国女性被诊断为乳腺癌。如果拟议的研究结果表明，有乳腺癌家族史的心理后遗症对HPA轴反应性的提高做出了重大贡献，这将表明，近亲患乳腺癌的经历可能会在其亲属被诊断患有癌症后的数年内产生生物学上的重大后果，并将开辟一个新的研究领域，研究这种责任感增加对更广泛的健康后果的影响。

DESCRIPTION (provided by applicant): For the healthy daughters and sisters of the 200,000+ women diagnosed with breast cancer each year in the U.S., the threat of this disease is particularly salient. Biologically, they are at risk for carrying genes that increase their likelihood of developing breast cancer. Even after accounting for BRCA1/2, women with breast cancer in their families (FH+) have at least twice the population risk. Psychologically, they are at risk for symptoms of anxiety, depression, and posttraumatic stress, even years after the diagnosis. An understudied possibility is that these women may also have heightened hypothalamic pituitary adrenal (HPA) axis (e.g., cortisol) responses to acute stress, a major pathway by which stress can affect health. The contributions of genetic and/or psychological factors to this heightened responsivity have not been investigated. The overall goal of the proposed research is to test the hypothesis that healthy women with family histories of breast cancer have heightened HPA axis stress responsivity, and to investigate the contributions of the genetic and psychological aspects of family histories to response variability. Healthy, FH+, premenopausal, working women and a frequency matched FH- sample will be recruited. After rigorous prescreening to reduce extraneous sources of variability, HPA axis stress responsivity will be evaluated in two well-established, tightly-controlled, stress paradigms: 1) a laboratory approach, the Trier Social Stress Test (high internal validity); and, 2) a 'real world' approach, work-stress in daily life (high external validity). Combined results of these approaches will be statistically examined (n=220 with complete data) to explore a broader model of family history effects on stress responsivity. Research aims of this psychobiological study are: 1) to investigate the relationship between family history of breast cancer and women's HPA axis responses to stress under controlled laboratory conditions; 2) to examine the relationship between family history of breast cancer and women's cortisol responses to stress under naturalistic conditions; 3) to evaluate the effects of genetic risk and psychological sequelae of having a family history of breast cancer on women's cortisol responses to stress under laboratory and naturalistic conditions, using structural equation analyses of combined data. PUBLIC HEALTH RELEVANCE: If the results of the proposed research indicate a significant contribution of the genetic aspects of family history to heightened HPA axis responsivity to stress, it would raise the possibility that inherited predispositions to responsivity in these women could be a contributing mechanism for their increased risk of developing breast cancer and would open up a new area of research into the etiology of this disease that is diagnosed in more than 200,000 American women each year. If the results of the proposed research indicate a significant contribution of the psychological sequelae of having a family history of breast cancer to heightened HPA axis responsivity, it would suggest that the experience of breast cancer in a close relative may have biologically significant consequences for years after their relative was diagnosed with cancer and would open up a new area of research into the broader health consequences of this increased responsivity.