CHARACTERIZATION OF BREAST CANCER DORMANCY IN BONE

这项提案的目的是识别处于休眠状态的癌细胞之间的基因差异 骨骼和那些已经从休眠状态“唤醒”的人，并发现负责的机制。 这些研究将为目前在中国的近300万乳腺癌患者确定潜在的治疗目标 减刑。有足够的证据表明缺氧(缺氧)刺激甲状旁腺激素相关。 蛋白(PTHrP)并抑制乳腺癌细胞中的白血病抑制因子(LIF)信号转导，这可能控制 重新觉醒的过程。LIFR的缺失或PTHrP的过度表达会导致弱的 转移的乳腺癌细胞向侵袭性和高转移性细胞转移，这导致了低氧的假设 促进骨转移的部分原因是通过下调LIFR信号，从而刺激癌细胞 通过产生血管内皮生长因子(VEGF)来解除休眠。这将使用以下几个工具进行测试 目前的乳腺癌模型中LIF和PTHrP信号被干扰以确定它们对mRNA水平的影响 乳腺癌细胞从休眠状态演变为增殖状态时的变化。弱转移性骨转移患者 McF-7和小鼠D2.0R癌细胞株将被用作乳腺癌在骨中休眠的模型。这些 在体内，通过抑制LIF信号和PTHrP的过度表达，细胞将被驱离休眠。已贴上GF板 乳腺癌细胞将用随着细胞分裂而丢失的RFP进行染色，这些标签将用于 对骨髓中分裂的休眠细胞和后休眠(增殖)细胞进行RNA测序。这项建议 我还将研究缺氧诱导因子(HIF)和LIF信号在骨骼原发肿瘤部位的作用 乳腺癌及HIF1α和HIF2α缺失小鼠自发转移模型的研究 乳腺。 约翰逊博士的近期目标是为骨骼中的乳腺癌细胞建立休眠特征 这在多种型号中都是一致的。拟议的项目将识别休眠VS中的遗传异常 并为约翰逊博士在一家学术机构建立独立实验室奠定了基础 研究机构。她的研究培训计划包括参加相关的研讨会、研讨会和 斯坦福大学主办的课程，以及来自共同导师和受人尊敬的职业咨询的监督 她成立了一个委员会，负责监督事业和科学发展。

This objective of this proposal is to identify genetic differences between cancer cells that lie dormant in the bone and those that have “re-awakened” from a dormant state, and to discover the mechanisms responsible. These studies will identify potential therapeutic targets for the nearly 3 million breast cancer patients currently in remission. There is sufficient evidence that hypoxia (a lack of oxygen) stimulates parathyroid hormone-related protein (PTHrP) and inhibits leukemia inhibitor factor (LIF) signaling in breast cancer cells, which may control the re-awakening process. Deletion of LIFR or over-expression of PTHrP results in the conversion of weakly metastatic breast cancer cells to invasive and highly metastatic cells, which leads to the hypothesis that hypoxia promotes bone metastasis in part through down-regulation of LIFR signaling, which stimulates cancer cells to exit dormancy through vascular endothelial growth factor (VEGF) production. This will be tested using several current breast cancer models in which LIF and PTHrP signaling is disrupted to determine their effect on mRNAlevel changes in breast cancer cells as they evolve from dormant to proliferative. Weakly bone metastatic human MCF-7 and mouse D2.0R cancer cell lines will be used as models of breast cancer dormancy in bone. These cells will be driven out of dormancy in vivo through LIF signalling inhibition and PTHrP over-expression. GFPlabelled breast cancer cells will be dyed with RFP that is lost as cells divide, and these tags will be used to fractionate dormant vs post-dormant (proliferative) cells in the bone marrow for RNA sequencing. The proposal will also examine the role of hypoxia inducible factor (HIF) and LIF signaling at the primary tumor site on bone metastasis using the MMTV-PyMT spontaneous model of breast cancer and mice lacking HIF1α and HIF2α in the mammary gland. Dr. Johnson’s immediate goal is to establish a dormancy signature for breast cancer cells in the bone that is consistent across multiple models. The proposed project will identify genetic aberrations in dormant vs proliferative cells and lay the foundation for Dr. Johnson to establish an independent laboratory at an academic research institution. Her research training program includes attendance at relevant seminars, workshops, and courses hosted by Stanford University, as well as oversight from co-mentors and a respected career advisory committee she has formed to monitor both career and scientific development.