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: 7992147
• 负责人: ELIZABETH A HOPPER-BORGE
• 金额: $ 18.98万
• 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/7992147
• 关键词: 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; 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; sialosyl-T antigen; 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）：细胞对化疗药物的耐药性是癌症治疗的主要障碍。治疗诱导的 ATP 结合盒 (ABC) 药物外排泵过度表达可促进许多药物治疗癌症的耐药性。虽然早期研究集中在 P-糖蛋白 (Pgp) 泵的过度表达和活性上，但一组结构独特的 ABC 外排泵，称为多药耐药蛋白 (MRP)，作为耐药性的替代来源越来越受到关注。我们最近表明，MRP7 与其他 MRP 不同，它赋予对多种抗癌药物的耐药性，包括紫杉烷类、长春花生物碱、埃博霉素 B 和核苷类药物。然而，人们对 MRP7 的体内作用知之甚少。在初步研究中，我们生成了 Mrp7-/- 敲除模型，并确定这些小鼠对紫杉醇治疗敏感，即使它们是 Pgp 的野生型，Pgp 被认为是主要的紫杉烷外排泵。在最近的一项合作研究中，我们表明，在培养细胞中，MRP7 活性受到拉帕替尼的抑制，拉帕替尼是一种 ErbB1/ErbB2 酪氨酸激酶受体的双重抑制剂，正在成为乳腺癌临床治疗中的常用药物。基于这些数据，我们假设 Mrp7 表达和活性可能是乳腺癌对药物治疗耐药性的迄今为止未被认识到的调节剂。为了测试这个想法，我们开发了两种乳腺癌模型。首先，我们将Mrp7-/-敲除小鼠与MMTV-多瘤病毒中T抗原（PyVMT）乳腺肿瘤模型杂交，从乳腺肿瘤中衍生细胞系，并开始耐药性分析。我们还开始将 Mrp7-/- 敲除小鼠与成熟的 MMTV-ErbB2/HER2/neu 小鼠模型进行杂交，该模型被认为是人类乳腺癌最具生理性的模型，并且还将从此模型中衍生出来自乳腺肿瘤的细胞系。我们提出了两个目标来研究 Mrp7 的体内作用，以及确定癌细胞中 MRP7 依赖性化疗耐药的机制。该提案的拟议目标是：1) 评估 MRP7 作为乳腺癌耐药因子，2) 确定拉帕替尼是否抑制 Mrp7 体内活性并进一步确定这种抑制的性质。我们的最终目标是确定 MRP7 表达是否可以用作特异性治疗的生物标志物，以及 MRP7 状态的知识是否可以用于开发改进的乳腺癌治疗策略。 公共健康相关性：将 MRP7 鉴定为乳腺癌体内化疗耐药因子将是全新的，并且与公共健康相关。我们的初步数据表明 MRP7 表达水平存在内在差异和药物选择差异，这表明 MRP7 的分析和靶向具有改善人类乳腺癌治疗的巨大潜力，这与 NCI 为癌症患者带来新疗法的使命直接相关。