MRP7 (ABCC10) as a Treatment Resistance Factor in Breast Cancer

MRP7 (ABCC10) 作为乳腺癌的治疗抵抗因子

• 批准号: 8091469
• 负责人: ELIZABETH A HOPPER-BORGE
• 金额: $ 22.09万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8091469
• 关键词: ABCB1 gene; ABCC1 gene; ABCG2 gene; ATP-Binding Cassette Transporters; Ablation; Address; Antineoplastic Agents; Attention; Binding; Biological Markers; Breast Cancer Cell; Breast Cancer Model; Cancer Patient; Cancer cell line; Cell Line; Clinical Management; Cultured Cells; Data; Depressed mood; Development; Dose; Drug Efflux; Drug resistance; Drug usage; ERBB2 gene; Epothilone B; Family member; Goals; Human; Knock-out; Knockout Mice; Knowledge; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Messenger RNA; Microtubules; Mission; Modeling; Mouse Mammary Tumor Virus; Mus; NF-kappa B; Nature; Nucleosides; P-Glycoprotein; P-Glycoproteins; PTEN gene; Paclitaxel; Pharmaceutical Preparations; Physiological; Polyoma Virus Middle T Staining Method; Protein Analysis; Protein Family; Proto-Oncogene Proteins c-akt; Public Health; Pump; Receptor Protein-Tyrosine Kinases; Regimen; Resistance; Role; Signal Transduction; Small Interfering RNA; Source; Taxane Compound; Testing; Therapeutic Agents; Treatment Protocols; Tumor Cell Line; Vinca Alkaloids; Viral Tumor Antigens; Wild Type Mouse; base; cancer cell; cancer therapy; chemotherapeutic agent; docetaxel; efflux pump; improved; in vivo; inhibitor/antagonist; lapatinib; malignant breast neoplasm; mouse model; novel; overexpression; public health relevance; resistance factors; response; taxane; treatment strategy; tumor

DESCRIPTION (provided by applicant): Cellular resistance to chemotherapeutic agents is a major obstacle to cancer treatment. Therapy-induced overexpression of ATP-binding cassette (ABC) drug efflux pumps promotes resistance in many drug-treated cancers. While early studies focused on overexpression and activity of the P-glycoprotein (Pgp) pump, a structurally distinct group of ABC efflux pumps, known as the Multidrug Resistance Proteins (MRPs), have been gaining increasing attention as alternative sources of resistance. We have recently shown that MRP7 is distinct from other MRPs in conferring resistance to a wide variety of anticancer agents including taxanes, vinca alkaloids, epothilone B and nucleoside-based agents. However, little is known about the in vivo role of MRP7. In preliminary studies, we generated an Mrp7-/- knockout model, and established that these mice are sensitized to treatment with paclitaxel even though they are wild type for Pgp, thought to be the major taxane efflux pump. In a recent collaborative study we showed that in cultured cells, MRP7 activity is inhibited by lapatinib, a dual inhibitor of the ErbB1/ErbB2 tyrosine kinase receptors that is becoming a common agent in clinical management of breast cancer. Based on these data, we hypothesize Mrp7 expression and activity might be a hitherto unappreciated modulators of breast cancer resistance to drug treatment. To test this idea, we have developed two breast cancer models. First, we have crossed Mrp7-/- knockout mice to the MMTV- Polyoma Virus middle T antigen (PyVMT) mammary tumor model, derived cell lines from the mammary tumors, and begun analysis of drug resistance. We have also begun crossing Mrp7-/- knockout mice to the well- established MMTV-ErbB2/HER2/neu mouse model, considered the most physiological for human breast cancer, and will also derive cell lines from mammary tumors from this model. We propose two Aims to investigate the in vivo role of Mrp7, as well to determine the mechanism of MRP7-dependent chemoresistance in cancer cells. The proposed aims this proposal will address are: 1) To assess MRP7 as a resistance factor in breast cancer and 2) determine if lapatinib inhibits Mrp7 in vivo activity and further define the nature of this inhibition. Our ultimate goals are to determine if MRP7 expression can be used as a biomarker for treatment specifically, and if the knowledge of MRP7 status can be used to develop improved treatment strategies for breast cancer. PUBLIC HEALTH RELEVANCE: The identification of MRP7 as an in vivo chemoresistance factor for breast cancer would be completely novel and is relevant to public health. Our preliminary data indicate both intrinsic and drug-selected variance in levels of MRP7 expression, suggesting analysis and targeting of MRP7 has considerable potential to improve treatment of human breast cancer and this is directly relevant to NCI's mission of bringing novel therapies to cancer patients.

描述（由申请人提供）：对化学治疗剂的细胞耐药性是癌症治疗的主要障碍。治疗引起的ATP结合盒（ABC）药物外泵的过表达促进了许多药物治疗的癌症的耐药性。尽管早期研究集中在P-糖蛋白（PGP）泵的过表达和活性上，但在结构上不同的ABC外排泵（称为多药耐药蛋白（MRP））的结构不同的泵一直在越来越多地作为抗药性来源。我们最近表明，MRP7与其他MRP不同，以赋予对各种抗癌剂的耐药性，包括紫杉烷，Vinca生物碱，Epothilone B和基于核苷的剂。但是，对MRP7的体内作用知之甚少。在初步研究中，我们产生了MRP7 - / - 敲除模型，并确定这些小鼠即使对PGP是野生型，也被认为是主要的紫杉烷外排泵，即使它们是紫杉醇的治疗。在最近的合作研究中，我们表明，在培养细胞中，Lapatinib抑制了MRP7活性，Lapatinib是ERBB1/ERBB2酪氨酸激酶受体的双重抑制剂，该抑制剂正成为乳腺癌临床管理中常见的药物。基于这些数据，我们假设MRP7表达和活性可能是迄今未批准乳腺癌对药物治疗的抗性调节剂。为了测试这个想法，我们开发了两个乳腺癌模型。首先，我们已经将MRP7 - / - 基因敲除小鼠跨越了MMTV-多瘤病毒中间T抗原（PYVMT）乳腺肿瘤模型，从乳腺肿瘤衍生出细胞系，并开始分析耐药性。我们还开始将MRP7 - / - 基因敲除小鼠越过良好的MMTV-ERBB2/HER2/NEU小鼠模型，该模型被认为是人类乳腺癌最生理的，并且还将从该模型中从乳腺肿瘤中得出细胞系。我们提出了两个目的，以研究MRP7的体内作用，以及确定癌细胞中MRP7依赖性化学抗性的机制。提出的目的该提案将解决：1）评估MRP7作为乳腺癌的抗性因素，2）确定拉帕替尼是否抑制了MRP7在体内活性中，并进一步定义了这种抑制的性质。我们的最终目标是确定MRP7表达是否可以用作特定治疗的生物标志物，以及是否可以使用MRP7状态的知识来开发改进的乳腺癌治疗策略。 公共卫生相关性：将MRP7鉴定为乳腺癌的体内化学抗性因素将是完全新颖的，并且与公共卫生有关。我们的初步数据表明，MRP7表达水平的内在和药物选择的方差表明MRP7的分析和靶向具有很大的潜力来改善对人类乳腺癌的治疗，这与NCI为癌症患者带来新疗法的使命至关重要。