Breast Cancer Risk: Analysis of heightened HPA axis stress responsivity

描述（由申请人提供）：对于美国每年被诊断患有乳腺癌的20多万名妇女中健康的女儿和姐妹来说，这种疾病的威胁尤为突出。从生物学上讲，她们携带的基因增加了患乳腺癌的可能性。即使考虑到BRCA1/2，家族中患有乳腺癌的女性（FH+）的风险至少是人群的两倍。在心理上，他们甚至在诊断后数年仍有焦虑、抑郁和创伤后应激症状的风险。一种尚未得到充分研究的可能性是，这些女性也可能对急性压力有更高的下丘脑-垂体-肾上腺（HPA）轴（例如皮质醇）反应，这是压力影响健康的主要途径。遗传和/或心理因素对这种高反应性的贡献尚未得到调查。本研究的总体目标是验证具有乳腺癌家族史的健康女性具有更高的HPA轴应激反应性的假设，并调查家族史的遗传和心理方面对反应变异性的贡献。健康、FH+、绝经前、职业妇女和频率匹配的FH样本将被招募。经过严格的筛选，以减少外来的变异性来源，HPA轴的压力反应性将在两个完善的，严格控制的压力范式中进行评估：1)实验室方法，特里尔社会压力测试（高内部效度）；2)一个“真实世界”的方法，日常生活中的工作压力（高外部效度）。将对这些方法的综合结果进行统计检验（n=220，完整数据），以探索家族史对应激反应影响的更广泛模型。本心理生物学研究的目的是：1)在实验室控制条件下，探讨乳腺癌家族史与女性HPA轴应激反应的关系；2)探讨自然条件下乳腺癌家族史与女性应激皮质醇反应的关系；3)利用组合数据的结构方程分析，评价乳腺癌家族史的遗传风险和心理后遗症对实验室和自然条件下女性应激皮质醇反应的影响。公共卫生相关性：如果提出的研究结果表明家族史的遗传方面对HPA轴对压力的反应有显著的贡献，那么这些女性的遗传反应倾向可能是她们患乳腺癌风险增加的一个贡献机制，并将为这种疾病的病因研究开辟一个新的领域，这种疾病每年在20多万美国女性中被诊断出来。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轴反应性的提高有重大贡献，这将表明，近亲患乳腺癌的经历可能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，研究这种增加的反应性对更广泛的健康后果。

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.