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

项目摘要 发育中的乳腺（MG）易受环境和生活方式风险因素的影响， 乳腺癌（BC）在成年后期的负担。因此，优化BC预防和护理需要寿命 方法来识别特定的早期生命风险因素，了解这些风险因素的潜在分子 促进癌症风险的机制，并设计适当的干预措施，减少成年期的BC。 利用Sprague-Dawley大鼠的人BC模型，我们已经建立了一个动态的和成功的 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， 了解生命早期的不良暴露如何导致成年期乳腺癌风险增加。我们发现 糖皮质激素（GC）对日常压力源的反应性因青春期和年轻时的社会隔离而提高 成年期，并与成人乳腺癌负担增加有关。此外，高GC 在青春期的反应损害导管发育和增加乳腺干细胞群，两个 这些特征与乳腺癌的增加有关。我们现在建议确定如何 升高的GC反应性破坏MG的发展，并通过检查潜在的 糖皮质激素受体（GR）激活与MG发育缺陷相关的分子机制 (Aim 1）。在目标2中，我们将介绍药物和社会环境干预， 成年后，以扭转应激反应加剧。我们预测这些干预措施将恢复正常的MG导管 分化，从而降低晚期癌症风险。在目标3中，我们将研究如何提高GC反应性 在青春期，不适当地保留了乳腺干细胞（MaSC）群体， 晚期癌症风险我们还将研究循环类固醇激素水平之间的关联， 结合其在MG微环境中的局部产生，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， 中断MG发展与随后的乳腺癌，并确定这些压力- 通过成年早期干预，介导的事件是可逆的。

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.