Targeting endocrine resistant breast cancer with anacardic acid

用漆树酸治疗内分泌耐药性乳腺癌

基本信息

批准号：
8368173
负责人：
Carolyn M. Klinge
金额：
$ 7.5万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-10 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8368173
关键词：
Acids Address Affect Anacardic Acids Androgen Receptor Animal Model Aromatase Inhibitors Binding Biological Assay Biological Availability Brazil Breast Breast Cancer Cell Breast Cancer Prevention Cancer Patient Carcinogens Cathepsins Cell Proliferation Cells Chemicals Chemoprevention Chemopreventive Agent Computer Simulation Consumption DNA DNA Binding DNA Binding Domain Data Development Diagnosis Diet Dietary Intervention Dietary Phytochemical Dietary intake Disease Disease Resistance Dose Elements Endocrine Epithelial Cells Estradiol Estrogen Receptor Modulators Estrogen Receptors Estrogen receptor positive Estrogens Female Food Gene Targeting General Transcription Factors Genetic Transcription Glucocorticoid Receptor Goals Growth Histology Human Hydrocarbons In Vitro Ingestion Juice Letrozole Ligands Liver neoplasms MCF7 cell Malignant Neoplasms Mammary Neoplasms Mammary Tumorigenesis Mammary gland Mediating Methods Methylnitrosourea Modeling Nuclear Receptors Nutrient Oral Outcome Measure Pathologic Patients Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Pilot Projects Postmenopause Progesterone Receptors Rattus Recurrence Reporting Resistance Resources Response Elements Route Selective Estrogen Receptor Modulators Serum Site Small Interfering RNA Source Specificity Sprague-Dawley Rats Staining method Stains Tamoxifen Testing Tissues Tocopherols Translational Research Tumor Tissue Woman Work Zinc Fingers base cancer risk human GATA1 protein in vivo indexing malignant breast neoplasm neoplastic cell overexpression physical property prevent receptor binding receptor function response small hairpin RNA transcription factor tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Dietary phytochemicals are potential sources of new drug leads to prevent breast and other cancers. Nuclear Receptor Alternative Site Modulators (NRAMs) are a recently defined class of chemicals with potential application in preventing breast cancer by blocking estrogen receptor ¿ (ER¿) function through mechanisms other than blocking ligand activation. NRAMs are distinct from currently used chemopreventives such as selective ER modulators (SERMs, e.g., tamoxifen (TAM)) and aromatase inhibitors (AI, e.g. letrozole) against which tumor cells become resistant. We recently reported that a purified anacardic acid (AnAc 24:1n-5) inhibited the proliferation of ER¿-positive/TAM-responsive MCF-7 and ER¿-positive/endocrine-resistant LCC9 and LY2 breast cancer cells, but not primary normal human mammary epithelial cells (HMECs). AnAc 24:1n-5 does not compete with [3H]estradiol (E2) for ER¿ or ER¿, but inhibits ER¿-DNA interaction and transcriptional activity with greater efficacy than ER¿. These data indicate that AnAc 24:1n-5 functions as a NRAM. AnAc 24:1n-5 is a congener of AnAc constituents found in caju juice (commonly consumed in Brazil) and thus establishes dietary intake as a relevant route for this potential NRAM. Our breast cancer cell-based work provides strong rationale for the proposed pilot study that addresses PAR-11-079 by 1) Investigating the mechanisms of action of AnAc as an NRAM by utilizing ER overexpression and shRNA knockdown approaches to confirm the specificity of AnAc 24:1n-5 as an NRAM. 2) Pilot testing and developing AnAc as a dietary intervention to prevent or retard carcinogen (NMU)-induced mammary tumors in female Sprague- Dawley (SD) rats. 3) Developing sensitive and reliable methods for analysis of AnAc and its metabolites in serum, tumors, and tissues. 4) Determining the bioavailability and dose-response of AnAc as "foods, nutrients, and other naturally-occurring food constituents". The hypotheses tested in these Specific Aims is that 1) AnAc acts as an ER-selective NRAM and 2) that AnAc, supplied orally in AIN-93M diet will function as a natural chemopreventive to NMU-induced primary mammary tumors in female SD rats. These studies will provide the first in vivo data regarding the efficacy of AnAc in primary mammary tumor prevention and will establish the serum and tissue levels of AnAc after oral consumption. PUBLIC HEALTH RELEVANCE: It is estimated that 230,480 US women will be diagnosed and 39,520 will die from breast cancer in 2011. The two goals of this project are 1) to determine if anacardic acid is a Nuclear Receptor Alternate Site Modulator (NRAM) that specifically inhibits estrogen receptor-DNA binding and 2) to test the ability of anacardic acid supplied dietarily to inhibit the development of NMU-induced mammary tumors in rats. This project the first to test AnAc 25:1n-5 as a NRAM to preventative carcinogen-induced breast cancer in an animal model.

描述（由申请人提供）：膳食植物化学物质是预防乳腺癌和其他癌症的新药的潜在来源核受体替代位点调节剂（NRAM）是最近定义的一类化学物质，可通过阻断雌激素受体来预防乳腺癌。 (ER¿) 通过阻断配体激活以外的机制发挥作用，与目前使用的化学预防药物不同，例如肿瘤细胞对其产生耐药性的选择性 ER 调节剂（SERM，例如他莫昔芬 (TAM)）和芳香酶抑制剂（AI，例如来曲唑）。我们最近报道了纯化的漆树酸 (AnAc 24:1n-5) 抑制 ER¿ -阳性/TAM反应性MCF-7和ER¿ - 阳性/内分泌耐药性 LCC9 和 LY2 乳腺癌细胞，但不包括原代正常人乳腺上皮细胞 (HMEC)，AnAc 24:1n-5 不会与 [3H]雌二醇 (E2) 竞争 ER¿或 ER¿ ，但抑制 ER¿ -DNA 相互作用和转录活性比 ER 更有效这些数据表明 AnAc 24:1n-5 具有 NRAM 的功能 AnAc 24:1n-5 是卡朱汁（在巴西常见）中发现的 AnAc 成分的同系物，因此将膳食摄入确定为这种潜在 NRAM 的相关途径。我们基于乳腺癌细胞的工作为拟议的试点研究提供了强有力的理由，该研究通过 1) 研究 AnAc 作为 NRAM 的作用机制。通过利用 ER 过表达和 shRNA 敲除方法来确认 AnAc 24:1n-5 作为 NRAM 的特异性 2) 试点测试和开发 AnAc 作为饮食干预措施，以预防或延缓女性 Sprague 中致癌物 (NMU) 诱发的乳腺肿瘤。 Dawley (SD) 大鼠 3) 开发用于分析血清、肿瘤和组织中 AnAc 及其代谢物的灵敏且可靠的方法。 AnAc 作为“食物、营养物质和其他天然存在的食物成分”的生物利用度和剂量反应在这些具体目标中测试的假设是 1) AnAc 作为 ER 选择性 NRAM，2) AnAc 口服提供。 AIN-93M 饮食将作为 NMU 诱导的雌性 SD 大鼠原发性乳腺肿瘤的天然化学预防剂，这些研究将提供有关 AnAc 功效的第一个体内数据。用于初级乳腺肿瘤预防，并将确定口服后 AnAc 的血清和组织水平。公共健康相关性：据估计，2011 年将有 230,480 名美国妇女被诊断出乳腺癌，39,520 名妇女将死于乳腺癌。该项目的两个目标是 1) 确定漆树酸是否是一种核受体替代位点调节剂 (NRAM)，特别是抑制雌激素受体-DNA 结合，2) 测试饮食中提供的漆树酸抑制NMU 诱发的大鼠乳腺肿瘤。该项目首次在动物模型中测试 AnAc 25:1n-5 作为 NRAM 来预防致癌物诱发的乳腺癌。