Targeting endocrine resistant breast cancer with anacardic acid

描述(申请人提供)：饮食中的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(NRAMs)是最近定义的一类化学物质，通过阻断配体激活以外的机制来阻断雌激素受体(ER)功能，从而在预防乳腺癌方面具有潜在的应用价值。NRAM不同于目前使用的化学保护剂，如选择性ER调节剂(SERM，例如他莫昔芬())和芳香化酶抑制剂(AI，例如来曲唑)，使肿瘤细胞对其产生抗药性。我们最近报道了一种纯化的Anac24：1N-5抑制ER阳性/反应的MCF-7和ER阳性/内分泌耐药的LCC9和LY2乳腺癌细胞的增殖，但对原代正常乳腺上皮细胞(HMEC)没有抑制作用。ANAC24：1N-5不与[~3H]雌二醇(E_2)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起NRAM的作用。ANAC 24：1N-5是在Caju果汁(巴西人通常消费)中发现的ANAC成分的同系物，因此确立了饮食摄入是这种潜在的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论基础，该研究针对PAR-11-079，通过1)通过利用ER过表达和shRNA下调方法来研究ANAC作为NRAM的作用机制，以确认ANAC 24：1N-5作为NRAM的特异性。2)中试和开发ANAC作为预防或延缓致癌物(NMU)诱导的雌性SD大鼠乳腺肿瘤的饮食干预措施。3)建立灵敏可靠的血清、肿瘤和组织中ANAC及其代谢物的分析方法。4)确定ANAC作为“食物、营养素和其他天然食物成分”的生物利用度和剂量反应。在这些特定目的中检验的假设是：1)ANAC作为ER选择性NRAM；2)在AIN-93M饲料中口服ANAC将对NMU诱导的雌性SD大鼠的原发乳腺肿瘤起到天然的化学预防作用。这些研究将提供有关ANAC在预防初级乳腺肿瘤中的有效性的第一个体内数据，并将确定口服后ANAC的血清和组织水平。

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.