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

项目总结(见说明)： 非裔美国人(AA)女性的乳腺癌发病率较低，但她们的乳腺癌发病率较高。 死亡率。此外，再生障碍性贫血妇女在目前接受治疗时预后较差。 可用的辅助化疗。三阴性乳腺癌(TNBC)是基底细胞样乳腺癌的一个亚型 占所有BC类型的近15%-20%的癌症，然而，它代表了在AA观察到的所有BC的45% 病人。TNBC肿瘤不依赖雌激素，具有非常侵袭性的临床行为，并且具有耐药性。 到目前可用的治疗方法。因此，发展TNBC可缩短无病生存期。 并增加AA乳腺癌(BC)患者的死亡率。解决这种生存差距将取决于 一旦确定有贡献的生物因素(S)，就可以转化为新的治疗方法。我们是 响应RFA-MD-11-002的要求，以解决以下主题： 非生物决定因素有助于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)证明了IGF-II激活了几个信号 增加生存蛋白的途径，以调节线粒体在BC细胞中诱导化疗耐药。 这些作用被白藜芦醇治疗(RSV)逆转，我们确定IGF-II被 引起线粒体细胞死亡的RSV。我们还发现来自再生障碍性贫血的乳腺肿瘤显著表达。 与高加索人相比，IGF-II、生存蛋白的水平更高，IGF信号通路的激活更高 女人。因此，我们推测，由于IGF-II促进BC细胞的化疗耐药，IGF-II的表达 肿瘤中的化疗药物将促进化疗耐药性，导致再生障碍性贫血患者之间的生存差异。 这一假说将通过四个具体的目标来检验：1：证明IGF-II在TNBC细胞系中的表达 诱导化疗耐药，2：确定哪些线粒体蛋白和信号通路介导 化疗耐药。目的3：建立一种小鼠模型，证明产生IGF-11的乳腺肿瘤 化疗耐药性和目标4：开展一项试点研究，以评估RSV对循环IGFII水平的影响， 以及内陆帝国中健康的非裔美国女性的生存蛋白。成功完成 我们高度协同的团队提出的研究将对治疗和 TNBC患者的生存，因为它将验证IGF-II作为化疗耐药的生物标志物，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(化疗反应性)。因此，改善治疗将有助于减少 死亡率，消除了观察到的TNBC患者之间的生存差异。

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.