(PQA1) Regulation of Metformin Response by Breast Cancer Associated Gene 2 (BCA2)

(PQA1) 乳腺癌相关基因 2 (BCA2) 对二甲双胍反应的调节

• 批准号: 8685444
• 负责人: QING PING DOU
• 金额: $ 19.84万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-13 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8685444
• 关键词: AMP-activated protein kinase kinase; Affect; Antidiabetic Drugs; Autophagocytosis; Breast; Breast Cancer Cell; Breast Cancer Treatment; Cancer Patient; Cell Survival; Chemicals; Chemopreventive Agent; Clinical; Clinical Data; Complex; Conflict (Psychology); Data; Event; FDA approved; Feedback; Fingers; Genes; Glycine decarboxylase; Homeostasis; IGF1 gene; IGF1R gene; In Vitro; Incidence; Institutes; Insulin; Light; Link; Malignant Neoplasms; Mammary Neoplasms; Measurement; Mediating; Metformin; Methodology; Molecular; Molecular Target; Mus; Outcome; Pathway interactions; Patients; Phase III Clinical Trials; Phosphotransferases; Preventive; Protein Biosynthesis; Proto-Oncogene Proteins c-akt; Raptors; Regulation; Regulatory Pathway; Research; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Staging; TSC1 gene; TSC2 gene; Testing; Time; Tumor Tissue; Ubiquitination; Work; Xenograft procedure; base; cancer cell; cancer prevention; cancer risk; cancer type; design; human FRAP1 protein; improved; inhibitor/antagonist; innovation; mTOR inhibition; malignant breast neoplasm; mouse model; novel; overexpression; prevention clinical trial; protein expression; public health relevance; response; treatment strategy; tumor; ubiquitin-protein ligase; upstream kinase

DESCRIPTION (provided by applicant): Breast Cancer Associated Gene 2 (BCA2) is a novel RING-finger ubiquitin E3 ligase that is overexpressed in >50% of breast tumors. AMPK is the master regulator of cellular energy homeostasis that has recently emerged as a promising molecular target in the treatment of breast and other cancers. Although the FDA- approved, AMPK activating, anti-diabetic drug metformin is in Phase III clinical trials, the benefit of AMPK activation remains controversial in various cancer types, due to lack of detailed mechanistic studies. We have found that metformin treatment of breast cancer cells induces BCA2 expression that then feedback inhibits the induced AMPK activation. Our discovery of this novel BCA2-AMPK regulatory pathway could explain why patients have various responses to metformin therapies, and suggests that metformin therapy when combined with a BCA2 inhibitor may be a more effective breast cancer treatment strategy than metformin alone. I In the current study, we hypothesize: (i) Metformin-mediated AMPK activation in human breast cancer cells triggers two conflicting signaling pathways: the well-known cancer-preventive/ tumor-suppressing signal via mTOR inhibition and the less-known cancer-survival feedback pathway via induction of the E3 ligase BCA2 activity that leads to degradation of a potential AMPK-activating kinase; (ii) Inhibition of BCA2-mediated feedback loop will increase the breast cancer-preventive effect of metformin. To test our hypotheses, we propose to study the role of BCA2 in metformin-induced, AMPK-mediated survival feedback loop in breast cancer cells (Aim 1), to identify the BCA2 substrate, a potential AMPK-activating kinase, and to study its function in metformin-induced survival feedback loop (Aim 2), and finally, to determine whether inhibition of BCA2 activity could increase breast cancer-preventive effect of metformin in mice (Aim 3). The successful completion of this project will significantly improve understanding of the molecular mechanisms of clinical metformin efficacy, help interpret the existing clinical data about various metformin efficacies in different cancer patients, and provide a scientific basis for designing rationalized metformin-based cancer prevention clinical trials. Our study could move the metformin research beyond the current correlative stages and establish, for the first time, detailed, mechanistic pathways that link tumor tissue BCA2 status to metformin efficacy and to changes that alter cancer incidence. This innovative proposal will: (i) study a previously unknown key component involved in the metformin- induced cancer cell survival feedback loop, the E3 ligase BCA2 that causes degradation of a potential tumor- suppressing AMPK-activating kinase; (ii) seek to shift the paradigms of current metformin research and its clinical use by means of a novel rationale and methodology for combining metformin with an inhibitor of BCA2 or AKT to increase the efficacy of metformin in breast cancer cells containing high levels of BCA2-mediated AMPK-inhibitory signal.

描述（由申请人提供）：乳腺癌相关基因 2 (BCA2) 是一种新型环指泛素 E3 连接酶，在 > 50% 的乳腺肿瘤中过度表达。 AMPK 是细胞能量稳态的主要调节因子，最近已成为治疗乳腺癌和其他癌症的有前景的分子靶点。尽管 FDA 批准的 AMPK 激活抗糖尿病药物二甲双胍正处于 III 期临床试验中，但由于缺乏详细的机制研究，AMPK 激活在各种癌症类型中的益处仍然存在争议。我们发现二甲双胍治疗乳腺癌细胞会诱导 BCA2 表达，然后反馈抑制诱导的 AMPK 激活。我们对这种新型 BCA2-AMPK 调节途径的发现可以解释为什么患者对二甲双胍治疗有不同的反应，并表明二甲双胍与 BCA2 抑制剂联合治疗可能是比单独使用二甲双胍更有效的乳腺癌治疗策略。 我 在当前的研究中，我们假设：（i）人类乳腺癌细胞中二甲双胍介导的 AMPK 激活触发了两条相互冲突的信号通路：众所周知的通过 mTOR 抑制的癌症预防/肿瘤抑制信号和鲜为人知的癌症生存信号通过诱导 E3 连接酶 BCA2 活性的反馈途径，导致潜在的 AMPK 激活激酶降解； (ii) 抑制 BCA2 介导的反馈环路将增强二甲双胍的乳腺癌预防作用。为了检验我们的假设，我们建议研究 BCA2 在二甲双胍诱导、AMPK 介导的乳腺癌细胞生存反馈环中的作用（目标 1），鉴定 BCA2 底物（一种潜在的 AMPK 激活激酶），并研究其作用目的是研究二甲双胍诱导的生存反馈环路中的功能（目标 2），最后确定抑制 BCA2 活性是否可以增加二甲双胍对小鼠的乳腺癌预防作用（目标 3）。 该项目的成功完成将显着提高对二甲双胍临床疗效分子机制的认识，有助于解读现有的二甲双胍在不同癌症患者中的疗效临床数据，为二甲双胍临床疗效的分子机制的认识提供科学依据。 设计合理的基于二甲双胍的癌症预防临床试验。我们的研究可以使二甲双胍研究超越当前的相关阶段，并首次建立将肿瘤组织 BCA2 状态与二甲双胍功效以及改变癌症发病率的变化联系起来的详细机制途径。 这项创新提案将：(i) 研究二甲双胍诱导的癌细胞生存反馈环中先前未知的关键成分，即 E3 连接酶 BCA2，它会导致潜在的肿瘤抑制 AMPK 激活激酶降解； (ii) 通过将二甲双胍与 BCA2 或 AKT 抑制剂相结合的新原理和方法，寻求改变当前二甲双胍研究及其临床应用的范式，以提高二甲双胍在含有高水平 BCA2- 的乳腺癌细胞中的功效。介导的 AMPK 抑制信号。