Breast Cancer Risk: Analysis of heightened HPA axis stress responsivity

乳腺癌风险：HPA 轴应激反应性升高的分析

• 批准号: 8307003
• 负责人: DANA H. BOVBJERG
• 金额: $ 37.55万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-10 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8307003
• 关键词: Accounting; Adrenal Glands; Affect; Age; American; Anxiety; Area; BRCA1 gene; BRCA2 gene; Biological; Characteristics; Circadian Rhythms; Data; Data Analyses; Daughter; Diagnosis; Disease; Early Diagnosis; Early treatment; Epidemiologic Studies; Equation; Ethnic Origin; Etiology; Family; Family history of; First Degree Relative; Frequencies; Fright; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Goals; Health; Hereditary Breast Carcinoma; Hydrocortisone; Hypothalamic structure; Laboratories; Life; Literature; Malignant Neoplasms; Mental Depression; Methodology; Modeling; Mutation; Pathway interactions; Patient Self-Report; Pituitary Gland; Population; Predisposition; Premenopause; Psychological Factors; Race; Recording of previous events; Recruitment Activity; Relative (related person); Research; Risk; Role; Sample Size; Sampling; Sampling Studies; Sister; Source; Stress; Surveys; Susceptibility Gene; Symptoms; Testing; Trier Social Stress Test; United States; Woman; Work; Working Women; acute stress; cancer risk; disorder risk; experience; hypothalamic-pituitary-adrenal axis; malignant breast neoplasm; psychobiologic; psychologic; psychological distress; research study; response; transmission process

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.

描述（由申请人提供）：对于美国每年超过 200,000 名被诊断患有乳腺癌的女性的健康女儿和姐妹来说，这种疾病的威胁尤为突出。从生物学上来说，她们有携带增加患乳腺癌可能性的基因的风险。即使考虑到 BRCA1/2，家族中患有乳腺癌的女性 (FH+) 的风险也至少是人群的两倍。从心理上来说，即使在诊断后数年，他们也面临着出现焦虑、抑郁和创伤后应激障碍症状的风险。一种未经充分研究的可能性是，这些女性的下丘脑垂体肾上腺 (HPA) 轴（例如皮质醇）对急性压力的反应也可能增强，这是压力影响健康的主要途径。遗传和/或心理因素对这种反应性增强的影响尚未得到研究。拟议研究的总体目标是检验以下假设：有乳腺癌家族史的健康女性会增强 HPA 轴应激反应性，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、FH+、绝经前、职业女性和频率匹配的 FH- 样本。经过严格的预筛选以减少外部变异来源后，HPA 轴压力反应性将在两种完善的、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）“现实世界”方法，日常生活中的工作压力（高外部效度）。这些方法的综合结果将进行统计检验（n=220，具有完整数据），以探索家族史对压力反应性影响的更广泛模型。这项心理生物学研究的研究目的是：1）在受控实验室条件下调查乳腺癌家族史与女性HPA轴对压力的反应之间的关系； 2）研究乳腺癌家族史与自然条件下女性皮质醇对压力的反应之间的关系； 3) 使用组合数据的结构方程分析，评估在实验室和自然条件下，遗传风险和有乳腺癌家族史的心理后遗症对女性皮质醇对压力的反应的影响。公共健康相关性：如果拟议研究的结果表明家族史的遗传因素对 HPA 轴对压力的反应性增强有显着影响，那么这些女性的遗传性反应倾向可能是导致她们患乳腺癌风险增加的一个机制，并将开辟一个新的研究领域，研究每年有超过 200,000 名美国女性被诊断出的这种疾病的病因。如果拟议研究的结果表明，具有乳腺癌家族史的心理后遗症对 HPA 轴反应性增强有显着贡献，则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多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，研究这种反应性增强所带来的更广泛的健康后果。