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

描述（由申请人提供）：乳腺癌是最常见的癌症形式之一，在美国每年诊断出超过180，000例新病例。 大约一半的乳腺癌患者死于这种疾病，因为转移性乳腺癌仍然是一种通常无法治愈和致命的疾病。 细胞毒性药物治疗是对抗癌症的重要武器。 然而，癌细胞经常对这些药物产生耐药性。 我们已经确定Ras/Raf/MEWERK信号转导级联的激活将导致MCF-7乳腺癌细胞在化疗药物阿霉素和紫杉醇存在下增殖的能力增加。Raf激活的后果可能包括药物转运蛋白mdr-1、抗乳腺癌bcl-2基因和自分泌生长因子（例如结合乳腺癌病因学中涉及的HER 2生长因子受体的双调蛋白）的表达增加。 在本研究中，我们将确定Ras/Raf/MEWERK信号转导通路诱导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的必要条件，以及这种情况发生的机制。为了实现这些目标，提出了三个具体目标：目标1。 确定Ras/Raf/MEWERK通路调节mdr-1、bcl-2和自分泌生长因子的机制，以及它们的诱导表达是否是乳腺癌耐药所必需的。 目的探讨Ras/Raf/MEWERK和Ras/PI 3 K/PTEN/PDK/Akt通路相互作用和调节mdr-1、bcl-2和乳腺癌耐药的机制。目标3： 确定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，将获得更多的信息，以治疗乳腺癌和其他癌症患者的药物组合，抑制信号转导和抗凋亡途径，导致耐药性。

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.