Mechanisms in IGF-ll induced Chemoresistance and Mitochondrial regulation in TNB

IGF-ll 诱导 TNB 化疗耐药和线粒体调节的机制

• 批准号: 8350951
• 负责人: DAISY D. DE LEON
• 金额: $ 19.21万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8350951
• 关键词: Accounting; Address; Adjuvant; Adjuvant Chemotherapy; African American; Animal Model; Antibodies; Apoptosis; Autocrine Communication; Basic Science; Behavior; Biological Assay; Biological Factors; Biological Markers; Blood; Blood specimen; Breast Cancer Cell; Breast Cancer Education; Cancer Center; Cancer Patient; Cancer cell line; Caucasians; Caucasoid Race; Cell Death; Cell model; Cells; Chemoprevention; Chemopreventive Agent; Chemoprotective Agent; Clinical; Clinical Research; Clinical Trials; Communities; Community Outreach; Confocal Microscopy; Development; Disease-Free Survival; Doctor of Pharmacy; Doctor of Philosophy; Doxorubicin; Epidemiology; Estrogens; Genes; Goals; High Prevalence; Human; Incidence; Instruction; Insulin Receptor; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Knowledge; Malignant Neoplasms; Mammary Neoplasms; Mediating; Mitochondria; Mitochondrial Proteins; Nude Mice; Oncologist; Outcome; Paclitaxel; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Pilot Projects; Proteins; Regulation; Research; Resistance; Resveratrol; Signal Pathway; Small Interfering RNA; Subgroup; Testing; Translating; Universities; Western Blotting; Wine; Woman; anticancer research; autocrine; chemotherapy; docetaxel; experience; health disparity; improved; in vivo; malignant breast neoplasm; minority health; mitochondrial membrane; mortality; mouse model; neoplastic cell; prevent; programs; response; survivin; treatment duration; treatment response; triple-negative invasive breast carcinoma; tumor; tumor growth

PROJECT SUMMARY (See instructions): African American (AA) women have a lower incidence of breast cancer, however they experience a higher mortality rate. Moreover, AA women are associated with worse outcomes when treated with currently available adjuvant chemotherapy. Triple negative breast cancer (TNBC) is a subgroup of basal-like breast cancer that accounts for nearly 15-20% of all BC forms, however, it represents 45% of all BC observed in AA patients. TNBC tumors are estrogen-independent, have a very aggressive clinical behavior and are resistant to currently available therapy. Thus, development of TNBC results in a reduced disease-free survival period and increased mortality of AA breast cancer (BC) patients. Addressing this survival disparity will depend upon identification of contributing biological factor(s) that can be translated into new treatments. We are responding to RFA-MD-11-002 to address the theme "The pathways and mechanisms by which biologic and non-biologic determinants contribute to or influence minority health or health disparities". Our breast cancer research team (LLU-COE NIMHD) demonstrated that IGF-II activates several signaling pathways to increase survival proteins that regulate the mitochondria inducing chemoresistance in BC cells. These effects were reversed by resveratrol treatment (RSV) and we determined that IGF-II was inhibited by RSV causing mitochondrial cell death. We also showed that breast tumors from AA express significantly higher levels of IGF-II, survival proteins and higher activation of the IGF signaling pathways than Caucasian women. Thus, we hypothesize that since IGF-II promotes chemoresistance in BC cells, expression of IGF-II in tumors will promote chemoresistance, contributing to the survival disparity observed among AA patients. This hypothesis will be tested by four Specific Aims: 1: Demonstrate that IGF-II expression in TNBC cell lines induces chemoresistance, 2: Determine which mitochondrial proteins and signaling pathways mediate chemoresistance. Aim 3: Develop a mouse model to demonstrate that IGF-ll-producing breast tumors are chemoresistant and Aim 4: Develop a pilot study to assess the effect of RSV on the levels of circulating IGFII, and survival proteins in healthy African American women in the Inland Empire. Successful completion of the proposed studies by our highly synergistic team will have a significant impact in the treatment and survival of TNBC patients because it will validate IGF-II as a biomarker for chemoresistance, will provide new IGF downstream targets to inhibit chemoresistance and will validate new biomarkers to assess response to chemotherapy (chemo-responsiveness). Consequently, improved treatment will contribute to reduced mortality, eliminating the survival disparity observed among TNBC patients.

项目摘要（参见说明）： 非裔美国 (AA) 女性乳腺癌发病率较低，但乳腺癌发病率较高 死亡率。此外，AA 女性在接受目前的治疗时，结果会更差。 可用辅助化疗。三阴性乳腺癌（TNBC）是基底样乳腺癌的一个亚组 癌症占所有 BC 形式的近 15-20%，但占 AA 中观察到的所有 BC 的 45% 患者。 TNBC 肿瘤不依赖于雌激素，具有非常侵袭性的临床行为并且具有耐药性 目前可用的治疗方法。因此，TNBC 的发展导致无病生存期缩短 AA 乳腺癌 (BC) 患者的死亡率增加。解决这种生存差距将取决于 确定可转化为新疗法的生物因素后。我们是 回应 RFA-MD-11-002，讨论主题“生物和药物的途径和机制” 非生物决定因素促成或影响少数群体的健康或健康差异"。 我们的乳腺癌研究团队 (LLU-COE NIMHD) 证明 IGF-II 可以激活多种信号传导 增加存活蛋白的途径，这些蛋白调节线粒体诱导 BC 细胞的化疗耐药性。 这些效应可通过白藜芦醇治疗 (RSV) 逆转，并且我们确定 IGF-II 被白藜芦醇治疗 (RSV) 所抑制。 RSV 导致线粒体细胞死亡。我们还表明 AA 的乳腺肿瘤显着表达 与白种人相比，IGF-II、存活蛋白水平更高，IGF 信号通路激活程度更高 女性。因此，我们假设由于 IGF-II 促进 BC 细胞的化疗耐药性，IGF-II 的表达 肿瘤中的药物会促进化疗耐药性，从而导致 AA 患者的生存差异。 该假设将通过四个具体目标进行检验： 1：证明 IGF-II 在 TNBC 细胞系中表达 诱导化疗耐药，2：确定哪些线粒体蛋白和信号通路介导 化学耐药性。目标 3：开发小鼠模型来证明产生 IGF-ll 的乳腺肿瘤是 耐化学性和目标 4：开展一项试点研究来评估 RSV 对循环 IGFII 水平的影响， 以及内陆帝国健康非裔美国女性的生存蛋白。顺利完成 我们高度协同的团队提出的研究将对治疗和治疗产生重大影响 TNBC 患者的生存，因为它将验证 IGF-II 作为化疗耐药性的生物标志物，并将提供新的 IGF 下游目标是抑制化疗耐药性，并将验证新的生物标志物以评估对化疗药物的反应 化疗（化疗反应）。因此，改善治疗将有助于减少 死亡率，消除了 TNBC 患者中观察到的生存差异。