The molecular basis of pregnancy-associated protection from breast cancer

与妊娠相关的乳腺癌预防的分子基础

• 批准号: 7943989
• 负责人: THOMAS Raymond GINGERAS
• 金额: $ 145.52万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7943989
• 关键词: Age; American; Area; Biological Assay; Biology; Breast Cancer Model; Carcinogens; Cell Aging; Cells; Clinical; Collection; Combined Modality Therapy; Comparative Study; DNA Methylation; DNA Resequencing; Development; Diagnosis; Disease; Disease Resistance; Drops; ERBB2 gene; Epidemiologic Studies; Epigenetic Process; Epithelial; Estrogens; Event; Exposure to; Future; Genome; Gland; Goals; Hormones; Human; Individual; Intervention; Laboratories; Lead; Libraries; Life; Malignant Neoplasms; Mammary gland; Maps; Masks; Memory; Methods; Methylation; Minor; Modeling; Molecular; Multiple Birth Offspring; Mus; Oncogenes; Oncogenic; Output; Pathway interactions; Patients; Pattern; Population; Pregnancy; Probability; Progesterone; Protocols documentation; RNA; Rattus; Relapse; Reporting; Research Design; Research Ethics Committees; Resolution; Resources; Risk; Risk Reduction; Roche brand of trastuzumab; Rodent; Running; Sampling; Selective Estrogen Receptor Modulators; Shotguns; Signal Transduction; Sorting - Cell Movement; Stem cells; United States; Variant; Woman; advanced disease; base; bisulfite; cancer risk; carcinogenesis; cell age; cell type; cohort; comparative; epigenomics; experience; falls; genome-wide; improved; lapatinib; malignant breast neoplasm; mortality; parity; protective effect; public health relevance; reconstitution; response; tumor; tumorigenesis; tumorigenic; volunteer

DESCRIPTION (provided by applicant): Each year, more than a million women are diagnosed with breast cancer, worldwide. Our understanding of the molecular mechanisms that underlie this disease are advancing rapidly, in part due to an enormous application of resources and effort to this problem. However, our understanding of how to modify the risk of developing breast cancer lags far behind. Epidemiological studies have demonstrated that a full-term pregnancy before the age of 30 provides a life-long reduction in the risk of developing the most common form of breast cancer, luminal ER+/PR+ disease. The effect is not minor, with a drop of nearly 50% in the probability of developing disease. This is a highly conserved phenomenon, since both rats and mice are afforded a similar, or even greater protection, by pregnancy or by a course of treatment with pregnancy-associated hormones. Mammary epithelial stem cells give rise to all of the cell types in the gland. When the gland involutes after pregnancy, it is thought that the only cells that survive to give rise to the remodeled post-partum gland are the stem cells themselves. Thus, these likely preserve some epigenetic memory of the pregnancy event. We propose that this memory modifies the ability of these cells, or their estrogen-responsive progeny, to become tumorigenic in response to oncogenic insults. We will map the complete epigenetic state of the mammary stem cell genome in nulliparous mice and humans. We will then search for changes in the epigenome that occur upon pregnancy or upon treatment (in mice) with a course of pregnancy associated hormones. We will correlate these with changes in the transcriptional output of short and long RNAs. It is our hope that these comparative studies will focus us on pathways that underlie protection and that we will be enabled in the long run to devise a clinical intervention that will substitute for the beneficial protective effects of early pregnancy. PUBLIC HEALTH RELEVANCE: More than a million women each year are diagnosed with breast cancer. Numerous epidemiological studies over the past 40 years have established that an early, full-term pregnancy reduces the risk of the most common form of breast cancer by half, and an even greater reduction in risk can be produced in rodents by pregnancy or a course of hormone treatment. We propose to identify common epigenetic changes that occur upon pregnancy or hormone exposure in humans and mice to identify candidate mechanisms for breast cancer risk reduction.

描述（由申请人提供）：全世界每年有超过一百万妇女被诊断患有乳腺癌。我们对这种疾病的分子机制的理解正在迅速发展，部分原因是对这个问题的资源和努力的巨大应用。然而，我们对如何改变患乳腺癌风险的理解远远落后。流行病学研究表明，30岁之前的足月妊娠可终身降低患最常见形式的乳腺癌（管腔ER+/PR+疾病）的风险。效果不小，发病概率下降近50%。这是一种高度保守的现象，因为大鼠和小鼠都通过妊娠或妊娠相关激素治疗过程获得了类似甚至更大的保护。乳腺上皮干细胞产生腺体中的所有细胞类型。当怀孕后腺体退化时，人们认为唯一存活下来的细胞是干细胞本身。因此，这些可能保留了一些怀孕事件的表观遗传记忆。我们认为这种记忆改变了这些细胞或其雌激素敏感后代对致癌性损伤的致瘤性。我们将绘制未生育小鼠和人类乳腺干细胞基因组的完整表观遗传状态。然后，我们将寻找在怀孕后或在用怀孕相关激素治疗（小鼠）时发生的表观基因组的变化。我们将把这些与短RNA和长RNA转录输出的变化联系起来。我们希望，这些比较研究将使我们关注保护的基础途径，并使我们能够在长期内设计一种临床干预措施，以取代早孕的有益保护作用。 公共卫生相关性：每年有超过一百万妇女被诊断患有乳腺癌。过去40年来的许多流行病学研究已经确定，早期足月妊娠可将最常见的乳腺癌风险降低一半，而啮齿动物通过妊娠或激素治疗过程可使风险降低更大。我们建议确定人类和小鼠在怀孕或激素暴露后发生的常见表观遗传变化，以确定降低乳腺癌风险的候选机制。