Ras/Raf & PI3K/Akt Induced Breast Cancer Drug Resistance

描述(申请人提供)：乳腺癌是最常见的癌症之一，在美国每年有超过18万例新诊断病例。大约一半的乳腺癌患者死于这种疾病，因为转移性乳腺癌通常仍然是一种不治之症和致命疾病。细胞毒药物治疗是抗癌的重要武器。然而，癌细胞经常对这些药物产生抗药性。我们已经确定，在化疗药物阿霉素和紫杉醇存在下，RAS/Raf/MEWERK信号转导通路的激活将导致MCF-7乳腺癌细胞增殖能力的增强。Raf激活的结果可能包括药物转运体MDR-1、抗凋亡基因bCL-2和自分泌生长因子的表达增加，如与HER2生长因子受体结合的两调节素，这些都与乳腺癌的病因有关。在拟议的研究中，我们将确定通过theras/Raf/MEWERK信号转导途径诱导MDR-1、bcl-2和自分泌生长因子的表达是否是诱导乳腺癌耐药所必需的，以及发生这种情况的机制。为了实现这些目标，已经提出了三个特定的目标：目的1.确定RAS/Raf/MEWERK通路调控MDR-1、bcl-2和自分泌生长因子的机制及其诱导表达是否是乳腺癌耐药所必需的，目的2.确定RAS/Raf/MEWERK和RAS/PI3K/PTEN/PDK/Akt通路相互作用和调节MDR-1、bcl2和乳腺癌耐药性的机制。目的3.探讨RAS/Raf/MEWERK通路影响乳腺癌细胞氧化还原状态以调节其对化疗药物敏感性的机制。通过这些研究，将有更多的信息用于乳腺癌和其他癌症患者的联合治疗，这些药物可以抑制导致耐药性的信号转导和抗细胞凋亡途径。

DESCRIPTION (provided by applicant): Breast cancer is among the most common forms of cancer with over 180,000 new cases diagnosed In the USA each year. Approximately half of all breast cancer patients die from the disease because metastatic breast cancer remains a generally incurable and fatal disease. Cytotoxic drug treatment is an important weapon against cancer. However, cancerous cells frequently develop drug resistance to these agents. We have determined that activation of the Ras/Raf/MEWERK signal transduction cascade will lead to an increased ability of MCF-7 breast cancer cells to proliferate in the presence of the chemotherapeutic drugs doxorubicin and paclitaxel. Consequences of Raf activation may include increased expression of the drug transporter mdr-1, the anti-apoptoticbcl-2 gene, and autocrine growth factors such as such as amphiregulin which bind the HER2 growth factor receptor implicated in the etiology of breast cancer. In the proposed studies, we will determine whether induction of mdr-1, bcl-2and autocrine growth factor expression by theRas/Raf/MEWERK signal transduction pathway is essential for induction of breast cancer drugResistance and the mechanisms by which this occurs. To achieve these objectives, three specific aims have been proposed: Aim 1. To determine mechanisms by which the Ras/Raf/MEWERK pathway regulates mdr-1, bcl-2, and autocrine growth factors and whether their induced expression is required for breast cancer drug resistance ,Aim 2. To determine mechanisms by which the Ras/Raf/MEWERK and Ras/PI3K/PTEN/PDK/Akt pathways interact and regulate mdr-1, bcl-2 and Breast cancer drug resistance. Aim 3. To determine mechanisms by which Ras/Raf/MEWERK Pathway influences the redox status of breast cancer cells to modulate their sensitivity to Chemotherapeutic drugs. Through these studies, more information will be available to treat breast and other cancer patients with combinations of drugs, which inhibit signal transduction and anti-apoptotic pathways leading to drug resistance.