TGF&, PI3K and HER2 Pathways in Breast Cancer Metastasis

项目1 乳腺癌转移中的TGF β、PI3K和HER2通路 负责人：Joan Massagu <$博士 关键人员：Swarnali Acharyya，博士，研究助理 邹一龙，研究生 项目概要： 即使在早期诊断并手术切除，乳腺癌也会在几个月内复发， 几十年的骨头，肺，肝和脑，以及局部。虽然五年无病生存率 在接受良好治疗的局限性乳腺癌患者中，89%的转移性疾病的出现几乎是 总是癌症死亡的预兆在P01基金的赞助下，我们发现了重要的 TGF β在三阴性（TN）和HER2+乳腺癌中的作用，以及PI3K通路的意外作用 和CXCR2信号在乳腺癌转移和化疗耐药性中的作用。进展包括：（一） 乳腺癌转移的小鼠模型，目前在世界各地的实验室中使用;（ii）TGF β通路的改变 从肿瘤抑制基因到转移促进基因;（iii）乳腺癌转移基因的鉴定， 途径;和（iv）发现肿瘤的自我播种过程，将肿瘤传播视为一种 多方向过程自上次竞争性续约以来，我们的工作照亮了 TGF β和PI3K通路在肿瘤发生和转移中的作用，并提高了对这些介质的兴趣， 播散性乳腺癌细胞的存活和耐药性。我们的具体目标1是确定 转化生长因子介导的转移。TGF？靶基因的鉴定介导了其前 转移作用将有助于靶向TGF β及其受体下游的转移。我们将使用新的 开发了TRAP技术，以鉴定宿主组织中乳腺转移癌细胞中TGF β调控的基因。 在具体目标2中，我们将定义PI3K-AKT和CXCR2的转移抑制能力。 抑制剂的我们最近的工作确定PI3K通路是微转移癌细胞的关键介质， 生存和保护恢复TGF β-依赖性肿瘤抑制，CXCR2信号作为一种免疫抑制剂， 乳腺癌细胞对化疗的重要防御。在与J. Baselga，S. 拉帕拉蒂湖Norton和N.罗森，我们将研究针对这些效应器的农业策略， 确定其对扩散性乳腺癌的有效性。我们的具体目标3是确定转移 HER2+乳腺癌的基因和功能。HER2+乳腺癌目前处于增加的危机中。 脑转移的发病率，但对分子驱动因素知之甚少。还有大量证据表明 TGF β增强了这种类型乳腺癌的转移。基于HER2+乳腺癌的新模型 转移，我们最近开发的，我们将确定驱动转移的基因，特别是 转移到脑，在HER2+乳腺癌，和TGF？在这个过程中的影响。链球菌我们将使用Lowe 创新的shRNA筛选技术，以功能表征候选转移基因。因此 本P01的继续集中在直接从我们最近的进展和依赖中出现的研究上。 关于与其他P01参与者合作对抗乳腺癌转移的进展。

Project 1 Title: TGF¿, PI3K and HER2 pathways in breast cancer metastasis Leader: Joan Massagu¿, Ph.D. Key Personnel: Swarnali Acharyya, PhD, Research Associate Yilong Zou, Graduate Student PROJECT SUMMARY: Even if diagnosed at an early stage and surgically removed, breast cancer can relapse within months to decades in bones, lung, liver and brain, as well as locally. Although the five-year disease free survival rate is 89% in patients with well-treated localized breast cancer, the appearance of metastatic disease is almost always a harbinger of eventual cancer mortality. Under the auspices of this P01 grant, we uncovered important roles the TGF¿ in in triple negative (TN) and HER2+ breast cancer, and unexpected roles of the PI3K pathway and CXCR2 signaling in breast cancer metastasis and chemoresistance. Progress includes (i) generation of mouse models of breast cancer metastasis, now used in labs worldwide; (ii) alteration of the TGF¿ pathway from tumor suppressor to metastasis promoter; (iii) identification of breast cancer metastasis genes and pathways; and (iv) discovery of the tumor self-seeding process, which views tumor dissemination as a multidirectional process. Since the last competitive renewal our work has illuminated the intersection of the TGF¿ and PI3K pathways in oncogenesis and metastasis, and heightened the interest on these mediators in the survival and chemoresistance in disseminated breast cancer cells. Our Specific Aim 1 is to identify mediators of TGF¿-driven metastasis. The identification of TGF¿ target genes that mediate its pro- metastatic action would help target metastasis downstream of TGF¿ and its receptors. We will use newly developed TRAP technology to identify TGF¿ regulated genes in breast metastatic cancer cells in host tissues. In Specific Aim 2 we will define the metastasis suppressive capacity of PI3K-AKT and CXCR2 inhibitors. Our recent work identified the PI3K pathway as a critical mediator of micrometastatic cancer cell survival and a protector against reinstated TGF¿-dependent tumor suppression, and CXCR2 signaling as an important defense of breast cancer cells against chemotherapy. In collaboration with J. Baselga, S. Chandarlapaty, L. Norton and N. Rosen, we will investigate farmacologic strategies targeting these effectors to define their effectiveness against disseminated breast cancer. Our Specific Aim 3 is to identify metastasis genes and functions in HER2+ breast cancer. HER2+ breast cancer is presently in a crisis of increased incidence of brain metastasis, yet little is known about the molecular drivers. There is also extensive evidence that TGF¿ enhances metastasis in this type of breast cancer. Based on new models of HER2+ breast cancer metastasis that we have recently developed, we will identify genes that drive metastasis, in particular metastasis to brain, in HER2+ breast cancer, and the impact of TGF¿ in this process. With S. Lowe we will use innovative shRNA screening techniques to functionally characterize the candidate metastasis genes. Thus, the continuation of the present P01 is focused on studies that directly emerged from our recent progress and rely on collaborations with the other P01 participants for the progress against breast cancer metastasis.