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

项目总结（见说明）： 非裔美国人（AA）女性乳腺癌的发病率较低，但她们的乳腺癌发病率较高。 死亡率此外，AA女性在接受目前的治疗时， 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%，然而，它占AA中观察到的所有BC的45%。 患者TNBC肿瘤是雌激素非依赖性的，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。因此，TNBC的发展导致无病生存期缩短 和AA乳腺癌（BC）患者的死亡率增加。解决这一生存差距将取决于 在鉴定出可转化为新治疗的起作用的生物因素后。我们 响应RFA-MD-11-002，讨论“生物和 非生物决定因素促成或影响少数群体的健康或健康差距”。 我们的乳腺癌研究小组（LLU-COE NIMHD）证明IGF-II激活了几种信号传导， 这些途径可以增加调节线粒体的存活蛋白，从而诱导BC细胞中的化学抗性。 这些作用被白藜芦醇处理逆转，我们确定IGF-II被白藜芦醇抑制。 RSV引起线粒体细胞死亡。我们还发现AA乳腺肿瘤表达显著 IGF-II、生存蛋白水平和IGF信号通路的激活程度高于高加索人 妇女因此，我们假设，由于IGF-II促进BC细胞的化学抗性，IGF-II的表达增加了BC细胞的化学抗性。 在肿瘤中的这种作用将促进化学抗性，从而导致在AA患者中观察到的存活差异。 该假设将通过四个特定目的进行检验：1：证明TNBC细胞系中IGF-II表达 诱导化学抗性，2：确定哪些线粒体蛋白和信号通路介导 化学抗性目的3：开发小鼠模型以证明产生IGF-II的乳腺肿瘤是乳腺癌的一部分。 目的4：开展一项初步研究，以评估RSV对循环IGFII水平的影响， 和生存蛋白的研究。成功完成 我们高度协同的团队提出的研究将对治疗产生重大影响， 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，将提供新的 IGF下游靶向抑制化疗耐药性，并将验证新的生物标志物，以评估对 化疗反应（chemo-responsibility）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。

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.