(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）：乳腺癌相关的基因2（BCA2）是一种新型的无名指泛素E3连接酶，在> 50％的乳腺肿瘤中过表达。 AMPK是细胞能量稳态的主要调节剂，最近在治疗乳腺癌和其他癌症方面已成为有前途的分子靶标。尽管FDA-批准，AMPK激活，抗糖尿病药物二甲双胍正在III期临床试验中，但由于缺乏详细的机械性研究，在各种癌症类型中，AMPK激活的好处仍然有争议。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。我们发现这种新型BCA2-AMPK调节途径可以解释为什么患者对二甲双胍疗法有各种反应，并表明与BCA2抑制剂结合使用时，二甲双胍治疗可能比单独使用二甲双胍更有效。 我 在当前的研究中，我们假设：（i）二甲双胍介导的人类乳腺癌细胞中的AMPK激活触发了两个相互矛盾的信号通路：众所周知的癌症预防/预防/肿瘤抑制信号通过MTOR抑制和鲜为人知的癌症 - 外观反馈途径通过E3 Ligase BCA2活性的诱导，导致A AM的启示 - DEGRASE A A A A A A AM诱导的反馈途径。 （ii）抑制BCA2介导的反馈环将增加二甲双胍的乳腺癌预防作用。 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小鼠中的二甲双胍（AIM 3）。 该项目的成功完成将显着提高人们对临床二甲双胍功效的分子机制的理解，有助于解释有关不同癌症患者各种二甲双胍效力的现有临床数据，并为科学基础提供了科学基础 设计基于二甲双胍的癌症预防临床试验。我们的研究可以将二甲双胍研究移至当前相关阶段，并首次建立详细的机械途径，这些途径将肿瘤组织BCA2状态与二甲双胍的效力联系起来，并与改变癌症发生率的变化。 该创新的建议将：（i）研究涉及二甲双胍诱导的癌细胞存活反馈环的先前未知的关键成分，这是导致潜在抑制AMPK激活激活激酶的降解的E3连接酶BCA2； （ii）试图通过一种新颖的原理和方法来改变当前的二甲双胍研究及其临床用途，以将二甲双胍与BCA2或AKT的抑制剂结合起来，以提高二甲双胍在含有含有大量BCA2介导的AMPK抑制AMPK抑制性AMPK抑制性信号的乳腺癌细胞中的疗效。