膳食源性染料木素长期摄入对乳腺癌化疗药物敏感性的影响

Dietary genistein has been marked as one of the most eyecatching phytoestrogens.As a typical Endocrine Disruptor（ED），it's role in carcinogenesis and development of estrogen sensitive cancer such as breast cancer is so far not clear.Our research group has proved that at physiological level, genistein could antagonize the anti-tumor activity of cisplatin in MCF-7 cells. Moreover, this effect would be affected obviously by the estrogen background. The present study, involving both in vitro/in vivo experiments and clinical study,is trying to take a round look on the impact of genistein on breast cancer's sensitivity to chemotherapy reagents ( such as paclitaxel &. cisplatin). Meanwhile, the influence of ER expression pattern and estradiol background will also be included. In this aspect,the pcDNA3.1(+)/ERβ and pGenesil-1-ERα-shRNA stable transfected MCF-7 cell model will be constructed, so as to enable us to change the ER expression pattern and investigate the role of ERα and ERβ in the genistein's activity. Furthermore,clinical tissue sample will be collected and exammed for mechanism exploring,especially on epigenetic level.Based on these, we intend to get a clear view on the effect of dietary genistein on chemotherapy sensitivity of breast cancer and to supply concrete data for individual dietary recommendation.

染料木素作为最具代表性的植物雌激素，是一种典型的外源性内分泌干扰物，其与乳腺癌发生发展之间的关系至今仍存在争议。本研究团队前期工作已证实低剂量染料木素在MCF-7细胞株内可明显拮抗顺铂的抗肿瘤活性且此效应与细胞所处的雌激素背景直接相关。本课题旨在从我国人群膳食习惯出发，全面考察膳食源性低剂量染料木素的长期摄入对于乳腺癌一线化疗药物（紫杉醇、顺铂）敏感性的影响。借由建立MCF-7 pcDNA3.1(+)/ERβ、pGenesil-1-ERα-shRNA稳定转染细胞模型，人为改变乳腺癌细胞雌激素受体表达模式以及模拟不同生理时期机体雌二醇内环境，考察ER受体表达状态以及机体雌激素背景对于染料木素生物学效应的影响。同时有针对性地结合临床病例，着眼于表观遗传学水平探索相关分子机制。从细胞以及整体水平，系统而深入地分析膳食因素与乳腺癌化疗效果之间的相互关系，为乳腺癌患者个体化膳食建议提供依据。

染料木素作为最具代表性的植物雌激素，是一种典型的外源性内分泌干扰物，其与乳腺癌发生发展之间的关系为人们所广泛关注。本研究团队从我国人群膳食习惯出发，从细胞水平、动物水平以及临床病例分析多个层面全面考察膳食源性低剂量染料木素的长期摄入对于乳腺癌发展以及其一线化疗药物（紫杉醇、顺铂）敏感性的影响。通过建立ERβKD MDA-MB-231等细胞模型，人为改变乳腺癌细胞雌激素受体表达模式以及模拟不同生理时期机体雌二醇内环境，考察ER受体表达状态以及机体雌激素背景对于染料木素生物学效应的影响；并且进一步通过建立去卵巢乳腺癌荷瘤裸鼠模型模拟绝经后ERα阳性乳腺癌患者开展动物实验以及临床样本分析，从整体水平考量染料木素膳食摄入对于乳腺癌患者病情发展以及化疗效果的影响。我们研究发现膳食水平的染料木素摄入后在体内分布不均一，其在移植瘤体内含量远高于血浆水平。在此浓度下，长期暴露于染料木素可促进乳腺癌细胞增殖，并显著影响紫杉醇以及顺铂的化疗效果。个体内雌激素本底水平以及瘤体内雌激素受体表达状态均可明显影响染料木素的负面生物学效应。希望以此为我国乳腺癌患者的个体化膳食指导以及相关风险评估提供重要数据并为合理利用膳食辅助临床治疗提供思路。