The molecular basis of pregnancy-associated protection from breast cancer

描述（由申请人提供）：每年，全世界有超过一百万的女性被诊断患有乳腺癌。我们对这种疾病的分子机制的理解正在迅速发展，部分原因是对这一问题的大量资源和努力的应用。然而，我们对如何降低患乳腺癌风险的理解远远落后。流行病学研究表明，在30岁之前足月妊娠可以终生降低患最常见的乳腺癌（腔内ER+/PR+疾病）的风险。效果不小，患病几率下降了近50%。这是一种高度保守的现象，因为大鼠和小鼠通过怀孕或使用与怀孕相关的激素进行一系列治疗，都获得了类似甚至更大的保护。乳腺上皮干细胞产生乳腺中所有类型的细胞。当腺在怀孕后消失时，人们认为唯一能存活下来形成产后腺的细胞就是干细胞本身。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反应后代的能力，使其在对致癌损伤的反应中成为致瘤性细胞。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，我们将寻找在怀孕或用怀孕相关激素治疗（小鼠）过程中发生的表观基因组变化。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集中在保护的基础途径上，并且从长远来看，我们将能够设计出一种临床干预措施，取代早期怀孕的有益保护作用。

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.