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Protein Kinase C Signaling and Breast Cancer

蛋白激酶 C 信号转导与乳腺癌

基本信息

批准号：
8018506
负责人：
Kaladhar B. Reddy
金额：
$ 27.44万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8018506
关键词：
Adverse effects Apoptosis Breast Breast Cancer Treatment Cancer Etiology Cell Line Cells Cessation of life Clinical Data Development Disease ERBB2 gene Estrogen Antagonists Estrogen Receptor Modulators Estrogen Receptor alpha Estrogens Future Growth Human In Vitro Intervention Investigation MAP Kinase Gene MCF7 cell Mammary Neoplasms Mediating Molecular Molecular Target Pathway interactions Pharmaceutical Preparations Play Protein Kinase C Proto-Oncogene Proteins c-akt Recurrence Regulation Relapse Resistance Role Signal Transduction Signaling Molecule Small Interfering RNA Staining method Stains Stream TNFSF10 gene Tamoxifen Testing Translating Woman base in vivo inhibitor/antagonist insight malignant breast neoplasm neoplastic cell novel overexpression prevent rottlerin treatment strategy tumor tumor growth tumor xenograft

项目摘要

Breast cancer is a leading cause of cancer death among women. Antiestrogen drugs, such as tamoxifen (Tam), are effective in the treatment of estrogen receptor alpha (ER)- positive breast tumors by slowing the growth of the tumors, preventing the recurrence of the disease, and with relatively few side effects. However, almost all responsive tumors eventually develop of Tarn-resistance. The mechanism(s) responsible for resistance and/or growth promoting effects of Tam are not clear at present. Studies from our group and others indicated estrogen-induced MARK activation (Erk1&2) is predominantly mediated by HRG/HER- 2/PKC-delta/Ras pathway. We have recently shown the following: (a) Three out of four antiestrogen resistant cell lines overexpress total and activated PKC-delta, (b) Overexpression of PKC-delta in Tarn-sensitive MCF- 7 cells leads to Tam-resistance both in vitro and in vivo, (c) Inhibition of PKC-delta by rottlerin or siRNA significantly reversed antiestrogen resistance, (d) Pretreatment of cells with rottlerin followed by TRAIL significantly enhanced apoptosis in antiestrogen resistant cells compared with sensitive cells in vitro, (e) PKC-delta levels are higher in Tarn-resistant tumors compared to Tam-sensitive tumors in MCF-7 tumor xenograft, (f) Immunohistochemical staining of Tarn-resistant human breast tumors showed a significant increase of PKC-delta levels compared with those in Tam-sensitive tumors. Based on the above results, we hypothesize that overexpression and/or activation of PKC-delta plays a major role in the regulation of antiestrogen resistance in ER-positive breast tumor cells. We are proposing the following four specific aims to test our hypotheses: Aim 1. We will determine the molecular mechanism by which PKC-delta overexpression and/or activation suppresses apoptosis in antiestrogen resistant cell lines. Aim 2. We will investigate how PKC-delta and/or its down stream signaling molecules regulate antiestrogen resistance. Aim 3. We will determine mechanism by which PKC-delta inhibitors) sensitizes antiestrogen resistant cells to TRAIL- induced apoptosis. Aim 4. We will develop treatment strategies to translate in vitro observations into practically applicable therapies in vivo. We anticipate that the proposed investigations would reveal novel insights into the mechanism by which PKC-delta regulates antiestrogen-resistance and the data should provide defined molecular target(s) for future clinical intervention for the treatment of breast cancer.

乳腺癌是妇女癌症死亡的主要原因。抗雌激素药物，例如他莫昔芬 (Tam)，通过减缓雌激素受体α（ER）阳性乳腺肿瘤的生长，肿瘤的生长，防止疾病的复发，并且副作用相对较少。然而，在这方面，几乎所有的响应性肿瘤最终都发展为Tarn抗性。负责的机制 Tam的抗性和/或生长促进作用目前尚不清楚。我们小组的研究，其他研究表明雌激素诱导的MARK激活（Erk 1和2）主要由HRG/HER介导。 2/PKC-δ/Ras通路。我们最近发现：（a）四分之三的抗雌激素耐药细胞系过表达总的和活化的PKC-δ，（B）在Tarn敏感的MCF-7细胞中PKC-δ的过表达。 7细胞导致体外和体内的TAM抗性。（c）通过rottlerin或siRNA抑制PKC-δ 显著逆转抗雌激素抗性，（d）用rottlerin预处理细胞，然后用TRAIL预处理细胞与体外敏感细胞相比，抗雌激素抗性细胞中的凋亡显著增强，（e）在MCF-7肿瘤中，与Tam敏感性肿瘤相比，Tam耐药肿瘤中的PKC-δ水平更高（f）Tar n抗性人乳腺肿瘤的免疫组织化学染色显示出显著的免疫抑制作用。与TAM敏感性肿瘤相比，PKC-δ水平增加。基于上述结果，我们假设PKC-δ过表达和/或激活在调节 ER阳性乳腺肿瘤细胞中的抗雌激素抵抗。我们提出以下四个具体目标为了验证我们的假设：目标1。我们将确定PKC-δ 过表达和/或活化抑制抗雌激素抗性细胞系中的凋亡。目标二。我们将研究PKC-δ和/或其下游信号分子如何调节抗雌激素抵抗。目的 3.我们将确定PKC-δ抑制剂使抗雌激素抗性细胞对 TRAIL诱导的细胞凋亡。目标4。我们将制定治疗策略，将体外观察结果转化为实际上适用于体内治疗。我们预计，拟议的调查将揭示新的深入了解PKC-δ调节抗雌激素抵抗的机制，数据应该为未来乳腺癌治疗的临床干预提供明确的分子靶点。