Effects of chronic pubertal stressors on mammary gland biology and cancer risk

项目摘要 发育中的乳腺(MG)容易受到环境和生活方式风险因素的影响，这些因素会增加 乳腺癌(BC)是成年后的负担。因此，优化BC预防和护理需要一个生命周期 识别特定早期生命危险因素的方法，了解这些危险因素的潜在分子 促进癌症风险的机制，并设计适当的干预措施，以减少成年后的BC。 利用SpragueDawley大鼠的人BC模型，我们建立了动态和成功的 乳腺癌生物学家、内分泌学家和生物心理学家之间的跨学科合作 了解不良的早期生活暴露如何导致成年后乳腺癌风险的增加。我们发现 糖皮质激素(GC)对日常应激源的反应性在青春期和青春期因社交孤立而增强 成年后，与成人乳腺癌负担增加有关。此外，更高的GC 青春期的反应性损害导管发育并增加乳腺干细胞数量，2 与乳腺癌增加有关的特征。我们现在建议确定如何 GC活性增强扰乱了MG的发育，并通过检查潜在的 糖皮质激素受体(GR)激活与MG发育缺陷的分子机制 (目标1)。在目标2中，我们将在早期引入药物和社会环境干预措施。 成年后可以逆转高度紧张的反应。我们预测这些干预将恢复正常的MG导管 分化，从而降低以后的癌症风险。在目标3中，我们将研究如何增强GC反应性 在青春期不适当地保存已知增加的乳腺干细胞(MASC)数量 后来有患癌症的风险。我们还将调查循环中的类固醇激素水平与 结合它们在MG微环境中的本地化生产，以及导管成熟和MASC 生物学。这些研究的完成将揭示新的应激介导的分子和细胞机制 阻断与随后的乳腺癌相关的MG的发展，并确定这些压力是否- 通过成年早期干预，调解的事件是可逆的。

PROJECT ABSTRACT The developing mammary gland (MG) is vulnerable to environmental and lifestyle risk factors that increase breast cancer (BC) burden in later adulthood. Therefore, optimizing BC prevention and care requires a lifespan approach to identify specific early life risk factors, to understand these risk factors’ underlying molecular mechanisms in promoting cancer risk, and to design appropriate interventions that reduce BC in adulthood. Using a Sprague-Dawley rat model of human BC, we have established a dynamic and successful transdisciplinary collaboration among a breast cancer biologist, an endocrinologist, and a biopsychologist to understand how adverse early life exposures lead to increased mammary cancer risk in adulthood. We find that glucocorticoid (GC) reactivity to everyday stressors is heighted by social isolation in puberty and young adulthood and is associated with increased adult mammary cancer burden. Moreover, heightened GC reactivity during puberty impairs ductal development and increases mammary stem cell populations, two characteristics that have been linked to increased mammary cancer. We now propose to determine how heightened GC reactivity disrupts MG development and increases cancer burden by examining the underlying molecular mechanisms connecting glucocorticoid receptor (GR) activation with MG developmental defects (Aim 1). In Aim 2 we will introduce both pharmacological- and social environmental-interventions in early adulthood to reverse heightened stress reactivity. We predict these interventions will restore normal MG ductal differentiation and thereby decrease later cancer risk. In Aim 3, we will examine how heightened GC reactivity during puberty inappropriately preserves mammary stem cell (MaSC) populations that are known to increase later cancer risk. We will also investigate the association between circulating steroid hormone levels, in conjunction with their localized production within the MG microenvironment, and ductal maturation and MaSC biology. Completion of these studies will uncover novel stress-mediated molecular and cellular mechanisms of disrupted MG development linked to subsequent mammary cancer and determine whether these stress- mediated events are reversible with early adulthood interventions.