TGF&, PI3K and HER2 Pathways in Breast Cancer Metastasis

项目1 乳腺癌转移中的转化生长因子β、PI3K和HER2通路 负责人：琼·马萨古博士。 主要人员：Swarnali Acharyya，博士，副研究员 邹亦龙，研究生 项目总结： 即使在早期诊断并手术切除，乳腺癌也可以在几个月内复发到 在骨骼、肺、肝脏和脑中，以及局部的几十年中。尽管五年无病存活率是 89%的局部乳腺癌患者在接受治疗后，几乎不会出现转移 总是预示着癌症的最终死亡。在这笔P01的资助下，我们发现了重要的 转化生长因子在三阴性(TN)和HER2+乳腺癌中的作用以及PI3K通路的意外作用 CXCR2信号在乳腺癌转移和化疗耐药中的作用。进展包括：(一)产生 乳腺癌转移的小鼠模型，目前在世界各地的实验室使用；(Ii)转化生长因子途径的改变 从肿瘤抑制者到转移促进者；(Iii)乳腺癌转移基因的鉴定和 (4)发现肿瘤的自我播种过程，认为肿瘤的扩散是一种 多方向的过程。自从上一次竞争性更新以来，我们的工作已经照亮了 转化生长因子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在 播散性乳腺癌细胞的存活率和化疗耐药性。我们的具体目标1是确定 转化生长因子β诱导的肿瘤转移的介体。介导转化生长因子前体的靶基因的鉴定 转移作用有助于靶向转化生长因子及其受体下游的转移。我们将使用新的 开发了TRAP技术来鉴定宿主组织中乳腺转移癌细胞中受转化生长因子调控的基因。 在特定的目标2中，我们将确定PI3K-AKT和CXCR2的转移抑制能力 抑制剂。我们最近的工作确认PI3K通路是微转移癌细胞的关键介质 存活和对恢复的转化生长因子依赖的肿瘤抑制的保护者，以及CXCR2信号作为一种 乳腺癌细胞对化疗的重要防御。与J.Baselga合作，S. ，我们将研究针对这些效应器的农学策略 确定它们对播散性乳腺癌的有效性。我们的具体目标3是识别转移 HER2+乳腺癌的基因和功能。HER2+乳腺癌目前处于增加的危机中 脑转移的发生率，但对分子驱动因素知之甚少。也有大量证据表明 在这种类型的乳腺癌中，转化生长因子会增加转移。基于HER2+乳腺癌新模型的研究 我们最近开发的转移，我们将识别驱动转移的基因，特别是 HER2+乳腺癌脑转移及转化生长因子在这一过程中的作用。对于S.Lowe，我们将使用 创新的shRNA筛选技术，以确定候选转移基因的功能。因此， 本报告的延续P01侧重于从我们最近的进展中直接出现的研究，并依赖 与其他P01参与者就对抗乳腺癌转移的进展进行合作。

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.