Regulation of Tumor Oxygenation by BACH1 in Breast Cancer

BACH1 在乳腺癌中对肿瘤氧合的调节

• 批准号: 10693966
• 负责人: MARSHA R ROSNER
• 金额: $ 39.83万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693966
• 关键词: Angiogenic Factor; Antioxidants; BACH1 gene; Blood flow; Breast Cancer Cell; Breast Cancer Patient; Breast cancer metastasis; Cancer Etiology; Cancer Patient; Catabolism; Cell Hypoxia; Cessation of life; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Cytotoxic Chemotherapy; Data; Disease; Drug Delivery Systems; ERBB2 gene; Endothelial Cells; Epigenetic Process; FDA approved; Gene Expression; Genes; Genetic Transcription; Goals; Heme; Hemin; Hormone Receptor; Hypoxia; Hypoxia Inducible Factor; Immunotherapy; Localized Malignant Neoplasm; Mediating; Metabolic; Mus; Oxygen; Oxygen Therapy Care; Patients; Pharmaceutical Preparations; Phenotype; Play; Production; Publishing; Radiation; Radiation therapy; Refractory; Regulation; Resistance; Role; Scheme; Signal Transduction; Specificity; Stress; Survival Rate; Testing; Therapeutic; Transcriptional Regulation; Treatment Efficacy; Tumor Oxygenation; Ubiquitin; Woman; Work; Xenograft procedure; aggressive breast cancer; angiogenesis; biological adaptation to stress; cancer cell; cancer subtypes; chemotherapy; cytotoxic; gene repression; improved; inhibitor; malignant breast neoplasm; migration; mortality; mouse model; multicatalytic endopeptidase complex; mutant; neoplastic cell; novel; novel therapeutic intervention; overexpression; oxidation; prognostic; programs; public health relevance; radiation resistance; response; small hairpin RNA; standard of care; transcription factor; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor hypoxia; tumor microenvironment

Triple negative breast cancer (TNBC), the most aggressive and metastatic subtype of breast cancer, is one of the major causes of cancer death in women. TNBC also has lower survival rates for primarily local cancers. Loss of hormone receptors and the lack of HER2 overexpression in TNBC limit treatments to cytotoxic therapies such as radiation, a key clinical strategy for 10-15% of breast cancer patients. Hypoxia is a major cause of resistance to radiotherapy, chemotherapy and even immunotherapy. Thus, identifying mechanisms to suppress the hypoxia stress response and increase the sensitivity of TNBC tumors to therapy remains a top clinical priority. Upon hypoxic stress, cancer cells initiate a transcriptional program that enables them to survive and migrate from an inhospitable microenvironment. While hypoxia-inducible factors (HIFs) are generally considered the main effectors, growing evidence suggests the hypoxia cellular response is much more complex and requires coordinated signaling with other stress response factors. One promising candidate is BACH1, a transcription factor that is induced by hypoxia and represses transcription of genes involved in heme oxidation and anti-oxidant production. Based on preliminary results, we now hypothesize that BACH1 is stabilized by hypoxia and functions as a key inducer of the cellular hypoxia response in TNBC cells leading to abnormal leaky vasculature that contributes to intratumoral hypoxia and radiation resistance. Specifically, we plan to: 1. Determine whether BACH1 is regulated by oxygen and induces a transcriptional hypoxic stress response in TNBC cells; 2. Determine whether BACH1 promotes angiogenesis, leaky vasculature and hypoxia in TNBC tumors; and 3. Determine whether BACH1 depletion sensitizes TNBC tumors to radiation. We propose that targeting BACH1 represents a unique strategy for increasing tumor oxygenation to improve the efficacy of cytotoxic, standard-of-care therapies such as radiation. Normalizing vasculature to suppress leakiness should also facilitate drug delivery to tumors. Since BACH1 can be targeted by an FDA approved drug either alone or in combination with HIF inhibitors, the proposed work could lead to a clinical trial in breast cancer and other cancer patients whose treatment involves radiation therapy.

三阴性乳腺癌(TNBC)是乳腺癌中最具侵袭性和转移性的亚型之一。 女性癌症死亡的主要原因。TNBC也有较低的存活率，主要是当地的 癌症。在TNBC中激素受体的丢失和HER2过表达的缺乏限制了治疗 放射等细胞毒性疗法是10%-15%的乳腺癌患者的关键临床策略。低氧 是抵抗放射治疗、化疗甚至免疫治疗的主要原因。因此，识别 抑制低氧应激反应和增加TNBC肿瘤对药物敏感性的机制 治疗仍然是临床上的首要任务。在低氧应激下，癌细胞启动转录程序， 使它们能够从不适宜居住的微环境中生存和迁徙。而低氧诱导因子 (HIF)通常被认为是主要的效应器，越来越多的证据表明，低氧细胞的反应是 要复杂得多，需要与其他应激反应因素协调信号。一件有希望的事 候选基因是BACH1，这是一种由低氧诱导并抑制基因转录的转录因子 参与血红素氧化和抗氧化剂的生产。根据初步结果，我们现在假设 BACH1受低氧稳定，是TNBC细胞低氧反应的关键诱导物 导致异常渗漏血管的细胞，导致肿瘤内缺氧和辐射 抵抗。具体来说，我们计划：1.确定BACH1是否受氧调节并诱导 TNBC细胞的转录低氧应激反应；2.确定BACH1是否促进血管生成， TNBC肿瘤的血管泄漏和缺氧；以及3.确定BACH1耗竭是否使TNBC增敏 肿瘤对辐射的影响。我们认为，靶向BACH1是增加肿瘤的一种独特策略 氧合以提高细胞毒性、标准护理疗法的疗效，如放射治疗。正规化 抑制渗漏的血管系统也应该促进药物向肿瘤的输送。由于BACH1可以成为目标 FDA批准的药物单独或与HIF抑制剂联合使用，拟议的工作可能导致 在乳腺癌和其他癌症患者中进行的临床试验，这些患者的治疗包括放射治疗。