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）阳性的乳腺癌是最常见的 乳腺癌是乳腺癌的一种亚型，占乳腺癌相关死亡的大多数。而ER+PR+乳腺 肿瘤最初可通过靶向内分泌疗法治疗，超过三分之一的患者将发展为 对治疗的抵抗此外，ER+乳腺癌在原发性肿瘤后>5年有复发的倾向。 去除，指示负责耐药性的休眠癌症干细胞（CSC）， 复发孕激素（P）在乳腺癌中的作用比雌激素研究较少;问题 关于激素替代疗法中使用的雌激素如何增加乳腺癌的风险， 绝经后妇女，以及P如何影响乳腺癌细胞的生物学。我们的实验室已经确定 P直接诱导一部分ER+PR+乳腺癌细胞变得更像CSC。这是由 几种乳腺干细胞标志物如细胞角蛋白5（CK 5）的表达，并伴有 增加乳腺球形成和肿瘤起始能力，并增强对化疗和化疗药物的抵抗力。 内分泌疗法尽管20世纪50年代的研究表明P调节细胞代谢， 尚未研究改变的代谢程序对PR转录活性的影响。 具体地，P抑制氧化磷酸化，氧化磷酸化是细胞内活性氧的主要来源。 cell.我们实验室的初步数据表明，P调节谷胱甘肽抗氧化系统， 丰富的活性氧和氮的清除剂。这是一个具有重要意义的发现， 因为乳腺CSC对氧化应激表现出更高的耐受性。我们的假设是P抑制了 氧化磷酸化以促进还原氧化还原状态，从而允许具有增加的GSH的CSC 抗氧化活性这些研究的目的是阐明P调节CSC的机制 在ER+PR+乳腺癌的人群中，并描述谷胱甘肽在切换这一开关中的作用。的 该建议的具体目标是确定1）氧化磷酸化的P调节，2）P信号传导如何 改变抗氧化作用，3）如果在ER+PR+乳腺癌中靶向谷胱甘肽， 治疗这些研究有可能确定代谢的脆弱性，以利用在靶向CSC ER+PR+乳腺肿瘤患者，最终目标是减少复发并改善患者 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.