Discovering genetic networks of triple-negative breast cancer

发现三阴性乳腺癌的遗传网络

• 批准号: 9265420
• 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 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9265420
• 关键词: Address; Biochemical Genetics; Breast Epithelial Cells; Cancer Model; Cancer Patient; Carcinoma; Cell Survival; Cells; Data; Disease; FDA approved; Functional disorder; Genetic; Genetic Screening; Genetic Transcription; Human; Impairment; 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; TP53 gene; Technology; Testing; The Sun; Therapeutic; Translating; Tumor Suppression; Tumor Suppressor Proteins; Tumorigenicity; Tyrosine Kinase Inhibitor; Ubiquitination; base; cancer cell; cancer genome; cancer initiation; cancer survival; cancer therapy; cell transformation; combat; cytotoxic; epigenome; functional restoration; genetic approach; in vivo; malignant breast neoplasm; metaplastic cell transformation; mouse model; neoplastic cell; novel; novel strategies; protein degradation; public health relevance; response; stability testing; targeted treatment; therapeutic evaluation; 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）是一种常见的侵袭性乳腺癌亚型，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分子驱动因素的了解不足。确定其失调驱动TNBC的信号网络将对我们对疾病的理解以及我们如何治疗患病患者产生巨大影响。最近，我们发现PTPN 12酪氨酸磷酸酶在TNBC中的肿瘤抑制作用（Sun等人，Cell 2011）。我们的数据表明PTPN 12在许多上皮癌中受损，包括超过70%的TNBC。内源性PTPN 12的缺失导致特异性原癌基因酪氨酸激酶的过度活化和随后的人乳腺上皮细胞（HMEC）的转化。PTPN 12在TNBC中经常通过转录后机制失活，并且恢复PTPN 12功能显著损害TNBC中的肿瘤进展和转移。这些研究表明PTPN 12作为人TNBC的抑制剂发挥功能。然而，控制PTPN 12功能的途径和PTPN 12抑制上皮癌如TNBC的机制知之甚少。我们建议定义PTPN 12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。具体而言，我们将解决以下关键问题：目的1：PTPN 12肿瘤抑制蛋白如何在TNBC中过度降解？我们的初步数据表明，PTPN 12在TNBC中通过超降解在蛋白质水平上显著失活。我们的证据表明PTPN 12是泛素化的，并且高度不稳定。我们将利用我们开发的新开发的遗传筛选工具来识别控制PTPN 12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生存中的作用。目的 2：小鼠和人三阴性乳腺癌中PTPN 12的再激活能否抑制体内肿瘤进展？PTPN 12蛋白在人TNBC中经常丢失，并且PTPN 12缺陷型TNBC的致瘤性和转移性响应于恢复PTPN 12而受损。我们将开发和测试PTPN 12缺陷的人和鼠TNBC的互补模型，并使用这些模型来描述PTPN 12抗TNBC特性的机制。目的3：PTPN 12功能障碍如何调节TNBC的存活？恢复PTPN 12表达是细胞毒性的，并损害TNBC肿瘤进展，表明PTPN 12抑制TNBC中的关键存活途径。从机制上讲，PTPN 12的缺失导致酪氨酸激酶（TK）cMET和PDGFR-β的联合过度活化。 我们将检验PTPN 12通过联合抑制cMET和PDGFR-β而损害TNBC进展的假设，这些PTPN 12调节的TK合作赋予PTPN 12缺陷型TNBC肿瘤存活。