Regulation of erbB2/Neu-induced mammary gland cancer

描述（由申请人提供）：过表达HER2/Neu的乳腺癌对抗激素治疗没有反应，并且比未表达的乳腺癌更具侵袭性。虽然使用Herceptin（一种人源化HER2/Neu单克隆抗体）可产生显著的临床反应，但许多患者对该治疗具有内在耐药性或预计会产生耐药性。了解HER2/Neu诱导肿瘤和调节其侵袭性的机制对于开发更有效的治疗方法至关重要。在这个提议中，我们描述了三个目标，使用基于细胞的测定和体内转基因小鼠模型，旨在确定由HER2/Neu启动的调控电路，最终在侵袭性乳腺癌的形成中表现出来。我们将研究肿瘤的三个主要调控成分，包括肿瘤/基质界面、HER2/Neu的细胞内信号靶点和转录节点。关于肿瘤/基质界面，我们发现TGF-(5)信号由于T-3RI的缺失而在致瘤进展的早期被抑制。相反，基质来源的激活素似乎激活了肿瘤周围的Smad2，激活素促进了分离的肿瘤细胞的迁移。在这个提议中，我们将确定激活素信号是否调节肿瘤的进展。关于细胞内信号传导中间体，我们发现mTOR抑制剂雷帕霉素可引起HER2/Neu肿瘤的消退，而不诱导细胞凋亡或血管塌陷。我们现在将确定雷帕霉素是否诱导肿瘤细胞过度自噬，以及肿瘤是否依赖于基础水平的自噬来生存。我们还将确定雷帕霉素是否调节HER2/Neu肿瘤的转移，以及抗HER2抗体治疗是否增强雷帕霉素的疗效。最后，我们将重点关注乳腺癌细胞中HER2/Neu和cyclin D1之间的转录调节因子LMO4。我们将确定肿瘤生长是否需要维持LMO4的表达，并确定该蛋白在HER2/ new诱导的肿瘤中的转录靶点。在完成这一提议后，我们将显著增加我们对激活素在肿瘤-间质通讯中的作用的理解，评估雷帕霉素治疗这些癌症的潜在效用，并评估LMO4在肿瘤发生中是否是一种专门的中间体。这些研究应该为开发合理设计的治疗HER2/ neu诱导乳腺癌的疗法揭示更多的靶点。

DESCRIPTION (provided by applicant): Breast cancers overexpressing HER2/Neu do not respond to anti-hormone therapy and are more aggressive than their non-expressing counterparts. While the use of Herceptin, a humanized monoclonal antibody to HER2/Neu results in significant clinical response, many patients have intrinsic resistance or are expected to develop resistance to this therapy. Understanding the mechanisms by which HER2/Neu induces tumors and regulates their aggressiveness will be critical for developing more effective therapeutics. In this proposal, we describe three aims using cell-based assays and an in vivo transgenic mouse model that are geared towards identifying the regulatory circuitry initiated by HER2/Neu that is ultimately manifest in the formation of aggressive mammary cancer. We will examine three major regulatory components of tumors including the tumor/stroma interface, intracellular signaling targets of HER2/Neu, and a transcriptional nodal point. Regarding the tumor/stroma interface, we found that TGF-(5 signaling is suppressed early during tumorigenic progression due to loss of T-3RI. In contrast, stromally-derived activin appears to activate Smad2 within the tumor periphery, and activin promotes migration of isolated tumor cells. In this proposal, we will determine if activin signaling regulates tumorigenic progression. With regard to intracellular signaling intermediates, we found that rapamycin, an inhibitor of mTOR, causes regression of HER2/Neu tumors without inducing apoptosis or vascular collapse. We will now determine if rapamycin induces excessive autophagy in tumor cells and if tumors rely on a basal level of autophagy for survival. We will also determine if rapamycin regulates metastasis of HER2/Neu tumors and if anti-HER2 antibody therapy potentiates the efficacy of rapamycin. Lastly, we will focus on a transcription regulator, LMO4, which is an intermediate between HER2/Neu and cyclin D1 in breast cancer cells. We will determine if maintenance of LMO4 expression is required for tumor growth as well as identify transcriptional targets of this protein in HER2/Neu-induced tumors. Upon completion of this proposal we will have significantly increased our understanding of the role of activin in tumor-stromal communication, evaluated the potential utility of rapamycin to treat these cancers, and assessed whether LMO4 is an obligate intermediate in tumorigenesis. These studies should reveal additional targets for development of rationally designed therapies for HER2/Neu-induced breast cancer.