植物雌激素真的能够治疗乳腺癌吗？
[摘 要] 植物雌激素是一类动物雌激素的类似物，作为一种双向的雌激素受体（estrogen receptor, ER）调节剂，能够有效地预防女性心血管疾病、改善更年期骨质疏松症及其他症状。植物雌激素与乳腺癌发生、发展的关系，是一个被广泛关注的问题。至今，已经进行了大量的体外实验、动物实验和流行病学调查研究，但结果莫衷一是。哈佛大学的Duffy教授及其同事在CA杂志发表文章，综述了植物雌激素与乳腺癌的关系。结论是：植物雌激素对乳腺癌的作用没有定论。我们认为Duffy等的结论与未充分考虑到ER的状态有关。植物雌激素通过ER发挥作用，因此，在评价植物雌激素的作用时，必须要考虑ER的状态（表达水平、亚型比例、基因的多态性以及细胞内的分布）。
[关键词] 雌激素；乳腺癌；植物雌激素
Effects of Phytoestrogen Depend on the Status of Estrogen Receptors
YU Jun1, *, CHEN Bao-ying2
(1 Experiment Teaching Center; 2 Radiology Department of Tangdu Hospital, Fourth Military Medical University, Xi’an 710032, Shaanxi, China)
[ABSTRACT] Phytoestrogens are a family of analogues of animal estrogen. As bidirectional mediators of ER (estrogen receptor), phytoestrogens are efficiently protective for females against cardiovascular diseases, and to ameliorate climacteric osteoporosis, as well as other symptoms. The relationship between phytoestrogens and breast caner is a question of public interest. Up to now, many experiments in vitro, animal experiments, and epidemic trials have been performed, however, there are discrepancies. Professor Duffy and colleagues from Harvard University published a literature in the Journal of CA. They reviewed the association between phytoestrogen and breast cancer, highlighting the uncertain effects of phytoestrogen on breast cancer. In our opinion, the conclusion of Duffy et al. is due to their neglect of ER status. Phytoestrogen functions via ER, thus the status of ER (expression levels, subtype ratio, polymorphism, and intracellular distribution) should be taken into account while evaluating effects of phytoestrogen.
[ KEY WORDS] Estrogen; Phytoestrogen; Breast cancer
植物雌激素是一类动物雌激素的类似物，作为一种双向的雌激素受体（estrogen receptor, ER）调节剂，能够有效地预防女性心血管疾病、改善更年期骨质疏松症及其他症状，而且比其他替代激素治疗的不良反应小。但究竟对乳腺起什么作用，仍然没有定论。
1. 雌激素及激素替代疗法
雌激素是由内分泌系统产生的类固醇激素。作为性激素，决定性别、维持第二特征。一方面，雌激素分泌不足可以造成骨质疏松、皮肤干燥、智力减退和心血管病等。雌激素替代疗法，以补充外源性雌激素来改善雌激素缺乏症状，为妇女延缓衰老作出了积极的贡献。而另一方面，雌激素分泌过量可以引起肥胖、焦虑、偏头痛和浮肿等症状，特别是乳腺癌发病的危险性增加。2002年6月9日，美国国家心肺血液研究所（NHLBI）宣布终止了激素替代疗法的研究项目，因为绝经后的妇女服用雌激素5年以上，将大大增加患乳腺癌的机会。这就提出了一个无法回避的问题——激素替代疗法是一把“双刃剑”，既能改善雌激素缺乏症状，延缓衰老；又有可能因雌激素水平过高导致乳腺癌的发生，以及带来其他副作用。因此，寻找新的雌激素替代物，实现既能延缓衰老，又能减少癌症发生及其他副作用，成为了人们的共识。
2. 植物雌激素及其双向调节作用
科学家们在植物当中发现一类分子结构与动物雌激素类似的物质，称之为植物雌激素。植物雌激素是存在于自然界植物中的杂环多酚类化合物，分为异黄酮（isoflavones）、木脂素（1ignans）和香豆雌酚（coumestrogens）三大类，其中，有关大豆异黄酮的研究最受关注。含植物雌激素的植物主要有：大豆、葛根和阿麻籽等。与动物雌激素不同，植物雌激素具有双向的调节作用：当内源性雌激素分泌不足时，植物雌激素可以发挥弱雌激素样作用；当内源性雌激素分泌过量时，起抗雌激素作用。目前，市场上和植物雌激素相关的保健品多如牛毛，号称“女性黄金”，令很多爱美女士趋之若鹜。
3. 植物雌激素与乳腺癌的关系
3.1 植物雌激素与乳腺癌的关系存在不确定性
植物雌激素与乳腺癌发生、发展的关系，植物雌激素是否具有保护作用，是一个被广泛关注的问题。至今，已经进行了大量的体外实验、动物实验和人群的流行病调查研究，但结果莫衷一是。细胞生物学、动物实验以及临床研究或人群调查研究都尚未能证实植物雌激素对女性乳腺和子宫内膜的安全性。植物雌激素对乳腺癌的预防或促进作用至今仍有争议。对此，哈佛大学的Duffy教授在CA杂志发表文章，进行了分析和总结，指出：研究数据显示，植物雌激素对于乳腺癌是否有保护作用，还存在争议。然而，女性在其青春期较多地摄入富含植物雌激素的大豆等食物，对于预防成年后患乳腺癌是有益的[1]。该文发表之后，受到相关领域学者广泛的关注和多次引用[2-5]。这是一篇综述性文章，Duffy列举了16项病例对照研究（case control studies），其中12项试验显示：大豆异黄酮的摄入和乳腺癌的危险性负相关，提示大豆异黄酮对于乳腺癌具有预防作用。然而，其他的病例对照研究没有发现大豆异黄酮对乳腺癌的防治作用。值得注意的是，Grace 等[6]发现尿液和血清大豆异黄酮的水平与乳腺癌的危险性正相关，这就对植物雌激素的安全性提出了质疑。提示我们：评价植物雌激素的作用时，不仅要考虑它的“治癌”效应，还要考虑到其可能的“致癌”效应。
另外，乳腺密度（Breast densit）是乳腺癌的重要危险因素之一，Duffy以此为衡量指标，总结了植物雌激素和乳腺密度的关系。一项来自新加坡的研究报道，对于绝经前和绝经后的妇女，大豆的摄入和乳腺密度的降低有关[7]。与之类似，一项针对美国绝经后妇女的研究也显示，植物雌激素降低乳腺密度[8]。但是，另外两项针对美国绝经前妇女的研究表明：分别补充大豆异黄酮[9]和食用大豆[10]，对于乳腺密度没有任何影响。而一项来自夏威夷和洛杉矶的绝经前妇女的前瞻性病例对照研究的结果却是：成年时大豆的摄入增加乳腺密度，而幼年时期大豆的摄入与成年后的乳腺密度负相关[11]。以上的报道表明：植物雌激素对于乳腺密度的作用也不明确，从而再次提示植物雌激素与乳腺癌关系的不确定性。
因此，Duffy的结论是：植物雌激素与乳腺癌的关系没有定论。植物雌激素在不同个体的体内表现出的活性差异较大。因为植物雌激素代谢的个体差异很大，此外，植物雌激素摄入者体内的内源性雌激素水平差异也对植物雌激素的作用有影响。另外，不同剂量的植物雌激素可能会产生不同的作用。在体外研究中发现，低浓度的染料木黄酮（<10μmoL/L）显示雌激素样效应，刺激ER阳性肿瘤细胞生长；但在较高浓度时（>10μmol/L），染料木黄酮却显示抗雌激素效应，抑制ER阳性肿瘤细胞的生长[12]。所以，Duffy认为植物雌激素与乳腺癌的关系没有定论的原因有三点：其一，植物雌激素的摄入难以标准化；其二，对于食物中植物雌激素的检测存在困难；其三，对于植物雌激素的代谢存在很大的个体差异。也就是说，主要由于这三种原因，造成以上谈到的临床试验的结论各执一端，莫衷一是。作者的分析有一定的道理，但是我们注意到，这三点原因的都是针对植物雌激素本身，而忽略了其赖以发挥作用的雌激素受体。
3.2 雌激素受体（estrogen receptors，ER）的状态在评价植物雌激素功能时具有重要意义
雌激素受体ER按照结构和功能的差异，分为a和β两种亚型。ERα多分布于乳腺、子宫等组织中，而ERβ多分布于中枢神经系统、骨、血管壁和泌尿生殖系统。植物雌激素是一类既有不完全雌激素效应，又有不完全雌激素拮抗作用的活性植物成分，其活性取决于其对体内ER的选择性结合。植物雌激素既可与ERa结合，也可与ERβ结合，但其与ERβ结合的亲和力以及活化作用要比与ERa大得多，所以被称为选择性的雌激素受体调节剂。例如大豆异黄酮主要通过激动ERβ发挥作用，而对于人体器官ERa 的激动作用还不清楚[13]。另外一种植物雌激素，染料木黄酮（genistein）对ERa的亲和力只有雌二醇的4 %，但与ERβ的亲和力却是雌二醇的87 %[14]。
雌二醇通过与ERα结合，刺激乳腺细胞和子宫内膜细胞增殖，对乳腺癌和子宫内膜癌发生起促进作用；而植物雌激素通过与ERβ结合，在靶组织发挥弱雌激素样作用。植物雌激素通常只具有很弱的雌激素活性，每摩尔的雌激素活性仅有17β雌二醇的1/10 000(大豆苷元)至1/100(香豆雌酚)。ERβ的激动剂对于MCF-7乳腺癌细胞系具有抑制效应[15,16]。目前，从染料木黄酮发展而来的，选择性的ERβ的激动剂已经成为新的抗乳腺癌药物[17].
像很多其他的受体与配体一样，植物雌激素与ER是一对在功能上密不可分“搭档”，离不了你，也少不了我。另外，ER的状态还可能发生变化。因此，在评价植物雌激素的作用时，必须要考虑ER的状态。包括表达水平、亚型比例、基因的多态性以及细胞内的分布。文献报道在培养的前列腺癌细胞系和乳腺癌细胞系[18,19]，小鼠的子宫[20]、乳腺[21]和肝脏[22]，以及乳腺癌病人[23]中，植物雌激素可以改变ER的表达水平。也就是说，ER的量会发生变化；那么，它的质有没有变化呢？有人检测了8种胰腺癌细胞系，结果发现植物雌激素可以使ERβ/ERα的比例发生变化[24]；另外，ER的基因多态性，也会影响到其功能[25]；除了量变和质变，某些外界干预因素如大豆提取物还可以改变ER在细胞内的分布[26]。
植物雌激素通过ER发挥作用，即植物雌激素效应的发挥依赖于ER的状态。并且，在进行植物雌激素干预的过程中，ER不是一成不变的，而会发生状态的变化。为此，我们针对Duffy的文章，撰写了一篇letter，得到CA杂志的认可，并全文刊出[27]。我们在文中指出雌激素受体ER与其配体一样重要，而这一点被作者忽略了。受体与其相应的配体是一对相互作用的矛盾，如果忽略了其中的一方，片面的评判另一方的作用，就会产生结论的偏颇。只有全面的考虑问题，才能够避免犯“顾此失彼”的错误。植物雌激素对乳腺癌作用的不确定性，恰恰说明了生命运动的复杂性，需要我们辩证的分析、判断。更重要的是，经过科学的实验加以证实。
参考文献：
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[27] Jun Yu, Libing Liu, Wei Wang, Jingguo Wei, Baoying Chen. Status of Estrogen Receptors During Administration of Phytoestrogen. CA Cancer J Clin. 20 May 2009.
附录A [摘自CA Cancer J Clin. 2009 May 20.]
Status of Estrogen Receptors During Administration of Phytoestrogen
Dear Editor,
As reviewed by Dr. Duffy and colleagues, there is conflict about the preventive role of phytoestrogen against breast cancer, due to differences in dietary measurement, lack of standardization of supplemental sources, differences in metabolism amongst individuals, and the retrospective nature of much of the research in this area [1]. In our opinion, the aforementioned problems are with phytoestrogen itself. However, the estrogen receptors (ER), which are equally as important as the ligands, are somewhat neglected.
Estrogen and ER are partners interacting with each other. Various examples in the literature provide evidence that phytoestrogen treatment regulates the expression levels of its receptor, ER, in cell lines [2,3], animals [4-7], and premenopausal patients with breast cancers [8]. Also, phytoestrogen could alter the ER intracellular distributions [9], as well as ER beta/alpha ratio [10]. In addition, there are polymorphisms of ER in the estrogen receptor gene [11]. In a trial of 138 Japanese women, ESR2 gene RsaI polymorphism appeared to modify the effects of phytoestrogen to reduce the risk of endometriosis [12].
Therefore, during administration of phytoestrogen, gene polymorphism and phytoestrogen-induced alteration of ER status might ultimately affect the exact role of phytoestrogen we want to clarify. This is worthy of investigation in the future.
Kind Regards,
Jun Yu, Ph.D. (1)
Libing Liu, M.D. Ph.D. (1)
Wei Wang, M.D. (2)
Jingguo Wei, M.D. (2)
Baoying Chen, M.D. Ph.D. (2)
1 Center of Teaching Experiment, School of Basic Medical Science, Fourth Military Medical University, Xi’an, Shaanxi, China; 2 Department of Radiology, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China Correspondence to: Dr. Baoying Chen, Department of Radiology, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Xi’an, Shaanxi, 710038, China. Tel.: 86-29-84777617, E-mail: yujunby@fmmu.edu.cn; Dr. Jun Yu, Center of Teaching Experiment, School of Basic Medical Science, Fourth Military Medical University, 169 Changle West Road, Xi’an, Shaanxi, China. Tel.: 86-29-84774766, E-mail: pclamper@163.com
References
[1] Duffy C, Perez K, Partridge A. Implications of phytoestrogen intake for breast cancer. CA Cancer J Clin. 2007;57(5):260-277.
[2] Stettner M, Kaulfuss S, Burfeind P, et al. The relevance of estrogen receptor-beta expression to the antiproliferative effects observed with histone deacetylase inhibitors and phytoestrogens in prostate cancer treatment. Mol Cancer Ther. 2007;6(10):2626-2633.
[3] Cappelletti V, Miodini P, Di Fronzo G, et al. Modulation of estrogen receptor-beta isoforms by phytoestrogens in breast cancer cells. Int J Oncol. 2006;28(5):1185-1191.
[4] Wu Y, Niwa K, Onogi K, et al. Effects of selective estrogen receptor modulators and genistein on the expression of ERalpha/beta and COX-1/2 in ovarectomized mouse uteri. Eur J Gynaecol Oncol. 2007;28(2):89- 94.
[5] Padilla-Banks E, Jefferson WN, Newbold RR. Neonatal exposure to the phytoestrogen genistein alters mammary gland growth and developmental programming of hormone receptor levels. Endocrinology. 2006;147(10):4871-4882.
[6] Shibayama T, Fukata H, Sakurai K, et al. Neonatal exposure to genistein reduces expression of estrogen receptor alpha and androgen receptor in testes of adult mice. Endocr J. 2001;48(6):655-663.
[7] Laurenzana EM, Weis CC, Bryant CW, et al. Effect of dietary administration of genistein, nonylphenol or ethinylestradiol on hepatic testosterone metabolism, cytochrome P-450 enzymes, and estrogen receptor alpha expression. Food Chem Toxicol. 2002;40(1):53-63.
[8] Touillaud MS, Pillow PC, Jakovljevic J, et al. Effect of dietary intake of phytoestrogens on estrogen receptor status in premenopausal women with breast cancer. Nutr Cancer. 2005;51(2):162-169.
[9] Zhao QW, Huang X, Lou YJ, et al. Effects of ethanol extracts from Adzuki bean (Phaseolus angularis Wight.) and Lima bean (Phaseolus lunatus L.) on estrogen and progesterone receptor phenotypes of MCF-7/BOS cells. Phytother Res. 2007;21(7):648-652.
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