Glutathione and redox state of progesterone-regulated breast cancer stem cells

项目摘要 雌激素受体(ER)和孕激素受体(PR)阳性的乳腺癌最常见 乳腺癌是乳腺癌的一种亚型，占与乳腺癌相关的死亡人数的大多数。而ER+PR+乳房 肿瘤最初可以通过有针对性的内分泌治疗来治疗，超过三分之一的患者会发展成肿瘤。 对治疗的抗拒。此外，ER+乳腺癌有在原发肿瘤后5年复发的倾向。 去除，表明休眠的癌症干细胞(CSCs)负责耐药和 复发。与雌激素相比，孕酮(P)在乳腺癌中的作用研究较少； 关于在激素替代疗法中使用孕激素如何增加乳腺癌风险的问题 绝经后妇女，以及P如何影响乳腺癌细胞的生物学。我们实验室已经鉴定出 P直接诱导一小部分ER+PR+乳腺癌细胞变得更像CSCs。这是由 几种乳腺干细胞标记物如细胞角蛋白5(CK5)的表达 增加乳房形成和肿瘤启动能力，并增强对化疗和 内分泌疗法。尽管20世纪50年代的研究表明磷调节细胞新陈代谢，但 代谢程序的改变对PR转录活性的影响尚未被研究。 具体地说，磷抑制氧化磷酸化，氧化磷酸化是体内活性氧物种的主要来源 手机。我们实验室的初步数据表明，磷对谷胱甘肽抗氧化系统的调节作用最大 富含活性氧和氮的清除剂。这是一项具有重要后果的发现， 乳腺干细胞对氧化应激表现出较高的耐受性。我们的工作假设是P抑制了 氧化磷酸化促进GSH升高的CSCs氧化还原状态的降低 抗氧化活性。这些研究的目的是解开P调节CSC的机制 ER+PR+乳腺癌中的人群，并描述谷胱甘肽在切换这一开关中的作用。这个 这一建议的具体目的是确定1)P对氧化磷酸化的调节，2)P如何信号转导 改变抗氧化作用，以及3)在ER+PR+乳腺癌中靶向谷胱甘肽是否会增强现有的 治疗。这些研究有可能确定针对CSC的代谢脆弱性。 ER+PR+乳腺肿瘤人群，最终目标是减少复发和改善患者状况 结果。

Project Summary Estrogen receptor (ER) and progesterone receptor (PR) positive breast cancers are the most prevalent subtype of the disease and constitute the majority of breast cancer-related deaths. While ER+PR+ breast tumors are initially treatable through targeted endocrine therapies, more than 1 in 3 patients will develop resistance to therapy. Moreover, ER+ breast cancers have a propensity to recur >5 years after primary tumor removal, indicative of dormant cancer stem cells (CSCs) that are responsible for drug resistance and recurrence. The role of progesterone (P) in breast cancer has been less studied than estrogens; questions remain about how progestin use in hormone replacement therapy increases breast cancer risk in postmenopausal women, and how P affects the biology of breast cancer cells. Our laboratory has identified that P directly induces a fraction of ER+PR+ breast cancer cells to become more like CSCs. This is marked by expression of several mammary stem cell markers such as cytokeratin 5 (CK5) and is accompanied by increased mammosphere formation and tumor initiation capacity, and heightened resistance to chemo- and endocrine therapies. Despite research from the 1950s showing that P modulates cellular metabolism, the influence of altered metabolic programming on the transcriptional activities of PR has not been investigated. Specifically, P suppresses oxidative phosphorylation, the primary source of reactive oxygen species within a cell. Preliminary data from our lab suggests that P modulates the glutathione antioxidant system, the most abundant scavenger of reactive oxygen and nitrogen species. This is a finding with important consequences, as breast CSCs display higher tolerance to oxidative stress. Our working hypothesis is that P suppresses oxidative phosphorylation to promote a reduced redox state permissive to CSCs with increased GSH antioxidant activity. The goal of these studies is to unravel the mechanism by which P regulates the CSC population within ER+PR+ breast cancer, and delineate the role of glutathione in toggling this switch. The specific aims of this proposal are to determine 1) P regulation of oxidative phosphorylation, 2) how P signaling alters antioxidant action, and 3) if targeting glutathione in ER+PR+ breast cancers will enhance existing therapies. These studies have potential to identify a metabolic vulnerability to exploit in targeting the CSC population in ER+PR+ breast tumors, with the ultimate goal of reducing recurrence and improving patient outcome.