SLEEP, CIRCADIAN HORMONAL DYSREGULATION AND BREAST CANCER SURVIVAL

睡眠、昼夜荷尔蒙失调与乳腺癌生存

• 批准号: 7717933
• 负责人: David Spiegel
• 金额: $ 0.17万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7717933
• 关键词: Address; Affective; Age; Aging; Anxiety; Anxiety Disorders; Breast Cancer Risk Factor; Cancer Etiology; Cancer Patient; Cessation of life; Circadian Rhythms; Computer Retrieval of Information on Scientific Projects Database; Corticotropin; Corticotropin-Releasing Hormone; Development; Disease; Disease Progression; Disruption; Elderly; Endocrine; Fatigue; Feeling; Functional disorder; Funding; Gene Expression; Grant; HPSE gene; Health; Homeostasis; Hormonal; Hormones; Human; Hydrocortisone; Immune; Immunologic Markers; Implant; Incidence; Institution; Lead; Life; Link; Long-Term Survivors; Longevity; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Melatonin; Mental Depression; Metastatic Neoplasm to the Breast; Modeling; Mus; Natural Killer Cells; Obstructive Sleep Apnea; Outcome; Pain; Patient Self-Report; Patients; Pattern; Physiological; Play; Postmenopause; Process; Prognostic Factor; Psychosocial Factor; Quality of life; Recovery; Research; Research Personnel; Resistance; Resources; Restless Legs Syndrome; Risk; Role; Sleep; Sleep Disorders; Sleeplessness; Social support; Source; Spouses; Stimulus; Stress; Structure; Substance abuse problem; Symptoms; System; Time; United States National Institutes of Health; Woman; body-mind; circadian pacemaker; coping; day; depressive symptoms; experience; hypothalamic-pituitary-adrenal axis; immune function; improved; malignant breast neoplasm; mortality; outcome forecast; psychosocial; relating to nervous system; shift work; tumor growth

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We spend one-third of our lives asleep, yet little research has been done on the effects of sleep on resistance to cancer incidence and progression. There is a high incidence (63%) of self-reported sleep disruption in women with breast cancer and this has been shown to be associated with decreased longevity in these patients. While this association could be driven by more severe cancer causing an increase in sleep disruption, it is also possible that sleep disruption could lead to decreased survival time in these patients. It has been shown that women whose sleep is disrupted by nighttime shiftwork are at higher risk for breast cancer. Other types of sleep disruption common in post-menopausal women, such as obstructive sleep apnea, restless legs syndrome, and insomnia, could also have significant deleterious effects on longevity. Sleep is a critical time for energy conservation and neural homeostasis. The disruption of these processes could, very likely, lead to dysfunction of the nervous, endocrine, immune and other systems. Furthermore, disrupted sleep is often treatable, providing a potentially powerful means of improving both the quality of life and the prognosis of cancer patients. A growing body of evidence suggests that psychosocial factors have potentially powerful modulating effects on the course of cancer. Sleep may play a central role. There is growing scientific evidence and increasing public concern regarding the link between stress and health. One of the major consequences of stress is disruption of circadian rhythms, including the timing and structure of sleep and hormonal activity. Recent research indicates that such disruption predicts poor prognosis for breast cancer patients, and thus may be a mediating mind-body mechanism linking stress to disease progression. Disrupted sleep is important for its immediate consequences, such as fatigue, development of depressive and anxiety disorders, increased substance abuse, and reduced social support from spouses/partners as well as for its long-term consequences. Sleep is essential to human functioning and to disease recovery. Sleep problems are persistent among long-term survivors of breast cancer, and are associated with a poorer quality of life. Undisturbed sleep appears essential for coping with cancer and symptoms such as pain, because disturbed sleep causes decrements in the functioning of physiological systems critical to cancer defense, such as natural killer cell activity and lowers the threshold for experiencing negative stimuli and feelings. However, little is known about specific affective or psychosocial factors that may precede or influence disrupted sleep for women with breast cancer. There were 211,300 new cases of breast cancer in the US in 2003 and 39,800 deaths due to the disease. Breast cancer is largely a disease of aging, rare below the age of 50, and increasingly common with advancing age. Recent research provides evidence that disrupted circadian rhythms are associated with increased risk of breast cancer incidence and faster progression to mortality. We have observed that loss of normal diurnal cortisol rhythm, with peaks late in the day rather than, as normal, in the morning, predicts early mortality with breast cancer. This disrupted rhythm is associated with more awakenings during the night, with the increased awakenings, perhaps, even contributing to the sustained disruption of the cortisol rhythm. Recent studies have shown that nighttime shift work is associated with a higher risk of developing breast cancer. In a murine model, disrupting circadian cycles, including cortisol, produced a doubling of implanted tumor growth. There is evidence that abnormal circadian clock gene expression is associated with cancer. Thus, sleep disruption is a potentially modifiable mediating risk factor for breast cancer and its progression. We therefore propose to study sleep disruption as a prognostic factor in the progression of metastatic breast cancer, and its association with disrupted circadian patterns of cortisol, corticotropin releasing factor (CRF), ACTH, melatonin, and measures of immune function. The project has four Specific Aims with 6 Hypotheses. To address Aim 1, we will compare sleep and diurnal hormone patterns in 105 women with metastatic breast cancer to 25 age- and SES-matched healthy controls. For Aim 2, we will study the association between the sleep patterns of these 105 women with metastatic breast cancer and various psychosocial and physiological factors. For Aim 3, we will examine the sleep patterns of these 105 women with metastatic breast cancer and follow them throughout the progression of their disease to determine whether disrupted sleep predicts shorter survival. For Aim 4, we will conduct exploratory mediator analyses to investigate whether sleep disruption mediates the relation of psychosocial factors (such as depression, anxiety) to health outcomes (HPA axis measures, immune markers and ultimately survival).

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 我们一生中有三分之一的时间都在睡眠中度过，但关于睡眠对抵抗癌症发生和进展的影响的研究却很少。 患有乳腺癌的女性自我报告的睡眠中断的发生率很高（63%），这已被证明与这些患者的寿命缩短有关。 虽然这种关联可能是由更严重的癌症导致睡眠中断增加造成的，但睡眠中断也有可能导致这些患者的生存时间缩短。 研究表明，睡眠因夜间轮班工作而受到干扰的女性患乳腺癌的风险更高。 绝经后女性常见的其他类型的睡眠障碍，如阻塞性睡眠呼吸暂停、不宁腿综合症和失眠，也可能对寿命产生显着的有害影响。 睡眠是能量保存和神经稳态的关键时间。 这些过程的破坏很可能导致神经、内分泌、免疫和其他系统功能障碍。 此外，睡眠中断通常是可以治疗的，这为改善癌症患者的生活质量和预后提供了潜在的强大手段。 越来越多的证据表明，心理社会因素对癌症进程具有潜在的强大调节作用。 睡眠可能发挥着核心作用。 越来越多的科学证据和公众越来越关注压力与健康之间的联系。 压力的主要后果之一是昼夜节律的破坏，包括睡眠的时间和结构以及荷尔蒙活动。 最近的研究表明，这种破坏预示着乳腺癌患者的预后不良，因此可能是一种将压力与疾病进展联系起来的调节身心机制。 睡眠中断因其直接后果（例如疲劳、抑郁和焦虑症的发展、药物滥用增加、配偶/伴侣的社会支持减少）及其长期后果而很重要。睡眠对于人体功能和疾病恢复至关重要。 睡眠问题在乳腺癌长期幸存者中持续存在，并且与较差的生活质量相关。 不受干扰的睡眠似乎对于应对癌症和疼痛等症状至关重要，因为不受干扰的睡眠会导致对癌症防御至关重要的生理系统功能下降，例如自然杀伤细胞活性，并降低经历负面刺激和感受的阈值。然而，对于可能先于或影响乳腺癌女性睡眠中断的特定情感或心理社会因素知之甚少。 2003年，美国新增乳腺癌病例211,300例，并有39,800人因此死亡。 乳腺癌很大程度上是一种衰老疾病，50 岁以下罕见，但随着年龄的增长越来越常见。最近的研究提供的证据表明，昼夜节律紊乱与乳腺癌发病风险增加和死亡加速相关。我们观察到，正常的昼夜皮质醇节律的丧失（在一天的晚些时候而不是像正常情况那样在早上达到峰值）预示着乳腺癌的早期死亡。这种节律紊乱与夜间醒来次数增多有关，而觉醒次数的增加甚至可能导致皮质醇节律的持续紊乱。最近的研究表明，夜班工作与患乳腺癌的风险较高有关。在小鼠模型中，扰乱昼夜节律周期（包括皮质醇）会导致植入肿瘤的生长加倍。有证据表明，生物钟基因表达异常与癌症有关。因此，睡眠中断是乳腺癌及其进展的一个潜在的可改变的介导危险因素。因此，我们建议研究睡眠中断作为转移性乳腺癌进展的预后因素，及其与皮质醇、促肾上腺皮质激素释放因子（CRF）、促肾上腺皮质激素、褪黑激素和免疫功能测量的昼夜节律模式破坏的关系。 该项目有 4 个具体目标和 6 个假设。为了实现目标 1，我们将比较 105 名患有转移性乳腺癌的女性与 25 名年龄和 SES 匹配的健康对照者的睡眠和昼间激素模式。对于目标 2，我们将研究这 105 名患有转移性乳腺癌的女性的睡眠模式与各种社会心理和生理因素之间的关联。对于目标 3，我们将检查这 105 名患有转移性乳腺癌的女性的睡眠模式，并在整个疾病进展过程中跟踪她们，以确定睡眠中断是否会导致生存期缩短。对于目标 4，我们将进行探索性中介分析，以调查睡眠中断是否介导心理社会因素（如抑郁、焦虑）与健康结果（HPA 轴测量、免疫标志物和最终生存）的关系。