Discovering genetic networks of triple-negative breast cancer

发现三阴性乳腺癌的遗传网络

• 批准号: 8847687
• 负责人: Thomas Westbrook
• 金额: $ 32.47万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8847687
• 关键词: Address; Biochemical Genetics; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast Cancer therapy; Breast Epithelial Cells; Cell Survival; Cells; Data; Disease; Disease Progression; Epithelial; FDA approved; Functional disorder; Genetic; Genetic Screening; Health; Human; Malignant Neoplasms; Methods; Modeling; Molecular; Mus; Neoplasm Metastasis; Oncogenic; PDGFRB gene; PTPN12 gene; Pathogenesis; Pathway interactions; Patients; Pre-Clinical Model; Property; Protein Tyrosine Kinase; Protein Tyrosine Phosphatase; Proteins; Proteomics; RNA Interference; Refractory; Regulation; Role; Signal Transduction; Structure; Technology; Testing; Therapeutic; Translating; Tumor Suppression; Tumor Suppressor Proteins; Tyrosine Kinase Inhibitor; Ubiquitination; base; cancer genome; cancer initiation; cell transformation; combat; cytotoxic; epigenome; functional restoration; genetic approach; in vivo; malignant breast neoplasm; metaplastic cell transformation; neoplastic cell; novel; novel strategies; protein degradation; response; stability testing; targeted treatment; tool; triple-negative invasive breast carcinoma; tumor; tumor initiation; tumor progression; tumorigenic; ubiquitin ligase

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.

描述（由申请人提供）：三阴性乳腺癌（TNBC）是乳腺癌的一种常见且具有侵袭性的亚型，目前的靶向治疗难以治愈。开发 TNBC 疗法的一个主要障碍是我们对 TNBC 的分子驱动因素缺乏了解。识别导致 TNBC 失调的信号网络将对我们对该疾病的理解以及如何治疗患病患者产生巨大影响。最近，我们发现 PTPN12 酪氨酸磷酸酶在 TNBC 中具有肿瘤抑制作用（Sun 等人，Cell 2011）。我们的数据表明 PTPN12 在许多上皮癌中受到损害，包括超过 70% 的 TNBC。内源性 PTPN12 的缺失会导致特定原癌酪氨酸激酶的过度激活以及随后人乳腺上皮细胞 (HMEC) 的转化。 PTPN12 在 TNBC 中经常通过转录后机制失活，恢复 PTPN12 功能可显着损害 TNBC 中的肿瘤进展和转移。这些研究表明 PTPN12 作为人类 TNBC 的抑制剂。然而，人们对控制 PTPN12 功能的途径以及 PTPN12 抑制 TNBC 等上皮癌的机制知之甚少。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 中如何过度降解？我们的初步数据表明，TNBC 中 PTPN12 在蛋白质水平上因过度降解而显着失活。我们的证据表明 PTPN12 是泛素化的并且高度不稳定。我们将利用新开发的基因筛选工具来识别控制 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 2：在小鼠和人类三阴性乳腺癌中重新激活 PTPN12 能否抑制体内肿瘤进展？ PTPN12蛋白在人类TNBC中经常丢失，并且PTPN12缺陷的TNBC的致瘤和转移特性因恢复PTPN12而受损。我们将开发和测试 PTPN12 缺陷的人类和小鼠 TNBC 的互补模型，并使用这些模型来描述 PTPN12 抗 TNBC 特性的机制。目标 3：PTPN12 功能障碍如何调节 TNBC 的存活？恢复 PTPN12 表达具有细胞毒性并损害 TNBC 肿瘤进展，表明 PTPN12 抑制 TNBC 中的关键生存途径。从机制上讲，PTPN12 的缺失会导致酪氨酸激酶 (TK) cMET 和 PDGFR-¿ 的联合过度激活。 我们将检验以下假设：PTPN12 通过联合抑制 cMET 和 PDGFR-¿ 来损害 TNBC 进展，并且这些 PTPN12 调节的 TK 协同作用，使 PTPN12 缺陷的 TNBC 中的肿瘤存活。