Discovering genetic networks of triple-negative breast cancer

描述（由申请人提供）：三阴性乳腺癌（TNBC）是一种常见的侵袭性乳腺癌亚型，目前的靶向治疗难以治愈。发展TNBC治疗的一个主要障碍是我们对TNBC分子驱动因素的理解不足。确定导致TNBC失调的信号网络将对我们了解这种疾病以及如何治疗患者产生巨大影响。最近，我们发现PTPN12酪氨酸磷酸酶在TNBC中具有抑瘤作用（Sun et al, Cell 2011）。我们的数据表明PTPN12在许多上皮性癌症中受损，包括超过70%的tnbc。内源性PTPN12的缺失导致特异性原致癌酪氨酸激酶的过度激活和随后的人乳腺上皮细胞（HMECs）的转化。PTPN12在TNBC中经常通过转录后机制失活，恢复PTPN12功能会显著损害TNBC的肿瘤进展和转移。这些研究表明PTPN12具有抑制人类TNBC的功能。然而，控制PTPN12功能的途径以及PTPN12抑制上皮性癌症如TNBC的机制尚不清楚。我们建议定义PTPN12肿瘤抑制网络的分子框架，并利用这些机制作为TNBC的治疗切入点。具体来说，我们将解决以下关键问题：目标1:PTPN12肿瘤抑制蛋白在TNBC中是如何超降解的？我们的初步数据表明，PTPN12在TNBC中通过超降解在蛋白质水平上显着失活。我们的证据表明PTPN12是泛素化的，高度不稳定。我们将利用新开发的遗传筛选工具来鉴定控制PTPN12泛素化和稳定性的调控网络的组成部分，并测试它们在细胞转化和TNBC存活中的作用。目的

DESCRIPTION (provided by applicant): Triple-negative breast cancer (TNBC) is a common and aggressive subtype of breast cancer that is refractory to current targeted therapies. A major barrier to developing TNBC therapies is the paucity in our understanding of the molecular drivers of TNBC. Identifying the signaling networks whose dysregulation drives TNBC would have enormous impact on our understanding of the disease and how we treat afflicted patients. Recently, we discovered a tumor suppressor role for the PTPN12 tyrosine phosphatase in TNBC (Sun et al, Cell 2011). Our data indicate PTPN12 is compromised in many epithelial cancers including more than 70% of TNBCs. Loss of endogenous PTPN12 leads to hyper-activation of specific proto-oncogenic tyrosine kinases and consequent transformation of human mammary epithelial cells (HMECs). PTPN12 is frequently inactivated in TNBC by post-transcriptional mechanisms, and restoring PTPN12 function dramatically impairs tumor progression and metastasis in TNBCs. These studies suggest PTPN12 functions as a suppressor of human TNBC. However, the pathways controlling PTPN12 function and the mechanisms by which PTPN12 suppresses epithelial cancers like TNBC are poorly understood. We propose to define the molecular framework of the PTPN12 tumor suppressor network and exploit these mechanisms as therapeutic entrypoints in TNBC. Specifically, we will address the following critical questions: Aim 1: How is the PTPN12 tumor suppressor protein hyper-degraded in TNBC? Our preliminary data suggest that PTPN12 is prominently inactivated in TNBC at the protein level by hyper-degradation. Our evidence indicates PTPN12 is ubiquitylated and highly unstable. We will exploit newly developed genetic screening tools that we developed to identify components of the regulatory network controlling PTPN12 ubiquitination and stability, and test their role in cellular transformation and TNBC survival. Aim 2: Can reactivation of PTPN12 in murine and human triple-negative breast cancers suppress tumor progression in vivo? PTPN12 protein is frequently lost in human TNBCs, and the tumorigenic and metastatic properties of PTPN12-deficient TNBC are impaired in response to restoring PTPN12. We will develop and test complementary models of PTPN12-deficient human and murine TNBC, and use these models to delineate the mechanisms of PTPN12 anti-TNBC properties. Aim 3: How does PTPN12 dysfunction regulate survival of TNBCs? Restoring PTPN12 expression is cytotoxic and impairs TNBC tumor progression, suggesting PTPN12 inhibits key survival pathways in TNBCs. Mechanistically, loss of PTPN12 leads to combined hyper-activation of the tyrosine kinases (TKs) cMET and PDGFR-¿. We will test the hypothesis that PTPN12 impairs TNBC progression by combined inhibition of cMET and PDGFR-¿, and these PTPN12-regulated TKs cooperate to confer tumor survival in PTPN12- deficient TNBCs.