摘要
背景:长时间高水平雌激素刺激已被公认为乳癌的致病危险因子。既往大量研究集中于雌激素与雌激素受体作用的途径;近年来,关于非雌激素受体途径致乳癌的研究屡见报道。在细胞内,雌激素,尤其是雌酮和17β-雌二醇可以被代谢为儿茶酚雌激素,继而被氧化为儿茶酚雌激素-半醌和儿茶酚雌激素醌类,后两者可以与DNA结合,使其突变而致癌。因此,机体中是否存在着某种保护机制来阻止这些有害儿茶酚雌激素的产生成为一个重要的问题。另外,硫酸化是雌激素代谢的重要途径,有研究显示一氧化氮可影响乳癌的生长、分化和转移。一氧化氮是否通过影响雌激素硫酸化从而降低雌激素代谢使乳癌风险增加,他莫昔芬是否通过影响一氧化氮的作用而起到抗乳癌的作用,目前未见报道。
目的:本研究的第一部分目的在于分析原发性乳癌患者乳癌组织中雌激素受体(Estrogen Receptor,ER)孕激素受体(Progesterone Receptor,PR)分布情况及绝经前后ER、PR分布的差别;第二部分探讨儿茶酚雌激素硫酸化与甲基化的关系;第三部分分析一氧化氮供体对雌激素硫酸化代谢的影响及他莫昔芬对一氧化氮作用的影响。
方法:第一部分:回顾性分析了2006年1月1日到2008年5月1日共145例于因原发性乳癌于北京医院手术的患者病理资料,分析其乳癌标本ER、PR的分布情况及绝经前后ER、PR的差别。第二部分:不同种类的儿茶酚雌激素加入到乳癌细胞MCF-7和人类乳腺上皮细胞MCF10A中,并用[~(35)S]标记,观察它们的硫酸化。第三部分:五种一氧化氮供体和17β-雌二醇加入到乳癌细胞MCF-7和人类乳腺上皮细胞MCF10A中,观察它们对17β-雌二醇的硫酸化的影响;将他莫昔芬、一氧化氮供体SIN-1,17β-雌二醇加入到MCF-7和MCF10A,检测他莫昔芬对一氧化氮作用的影响。
结果:
第一部分:自2006年1月1日至2008年5月1日于北京医院因原发性乳癌手术患者共145例,其中雌激素受体分布情况分别如下:ER(-)者共41例(占28.3%),ER(+)者共104例(占71.7%);PR(-)者共45例(占31.0%),PR(+)者共100例(占69.0%);绝经前后ER阳性率分别为66.7%和75%,PR阳性率分别为68.4%和69.3%,ER、PR的阳性率绝经后较绝经前略有上升,但并无统计学差异(P＞0.05)。第二部分:加入儿茶酚雌激素2-OH-E_1,2/4-OH-E_2后,在MCF-7和MCF10A细胞的培养液中产生并释放被甲基化+硫酸化的硫酸化2-甲氧基-E_1,2/4-甲氧基-E_2;而加入4-OH-E_1时,细胞的培养液中则可检测到被甲基化+硫酸化的硫酸化4-甲氧基-E_1和仅被硫酸化的4-OH-E_1。此结果显示了儿茶酚-O-甲基转移酶和细胞液硫酸化转移酶在儿茶酚雌激素代谢中存在着复杂的相互作用。酶学分析表明,在已知的人类11种细胞液硫酸化转移酶中,有五种硫酸化转移酶(SULT1A1,SULT1A2,SULT1A3,SULT1C4和SULT1E1)可以催化儿茶酚雌激素和甲氧基儿茶酚雌激素使之硫酸化,其中以SULT1E1的活性最强。第三部分:五种硝基化化合物(SNP,SNAP,SPONONATE,DETA,SIN-1)在MCF-7和MCF10A细胞中,均可降低17β-雌二醇硫酸化,并存在浓度依赖性。而他莫昔芬并不降低SIN-1这种作用。
结论:1、ER、PR阳性者占乳癌患者的多数,绝经后ER、PR阳性率较绝经前略有上升,但并无统计学差异。雌激素受体阴性的乳癌患者仍占乳癌患者的相当比例。雌激素受体途径外的乳癌的发病机制有待进一步研究。2、硫酸化是儿茶酚雌激素代谢的重要途径,儿茶酚-O-甲基转移酶和细胞液硫酸化转移酶可能在儿茶酚雌激素代谢和失活中具有联合作用。3、一氧化氮供体可以明显降低MCF-7和MCF10A中的雌激素硫酸化代谢,并且有明显的浓度依赖性,可能是一氧化氮增加乳癌发病风险的机制之一。而他莫昔芬对NO的作用并无影响,说明他莫昔芬的治疗乳癌途径可能与NO抑制雌激素硫酸化无关。
INTRODUCTION.Prolonged exposure to high level of estrogen is a well known risk factor for breast carcinogenesis.Most of the research focused on the estrogen and estrogen receptor(ER) approach.In cells,estrogens,in particular estrone(E_1) and 17β-estradiol(E_2), can be converted to catecholestrogens(CEs) which may be oxidized to form CE-semiquinones and CE-quinones that are capable of binding to DNA to induce mutations,followed by carcinogenesis.Whether the body is equipped with protective mechanisms against potentially harmful CEs,therefore,is an important issue.Sulfate conjugation is a major pathway for the biotransformation and excretion of estrogens.Nitric oxide(NO) may affect tumor growth, differentiation,metastasis capability.By now there are little evidences show that whether NO decreases estrogen metabolism by affecting estrogens' sulfation.The effects of tamoxifen (TAM) on NO to breast cancer remain unknown.
Purpose of this study:Part 1,To analyze the expression of estrogen receptor(ER), progesterone receptor(PR) in 145 breast cancer samples from patients and the correlation between the expression of ER,PR and menopause.Part2,To examine the relation between sulfation and methylation in the metabolism of CEs.Part 3,to measure the effects of NO Donors on estrogen sulfation by MCF-7 and MCF10A and to evaluate the influence of TAM on NO Donor effects.
MATERIALS AND METHODS.Part 1:We used immunohisto-chemical methods to detect the expression of ER and PR in 145 cases of breast cancer and the relation between ER, PR expression and menopause.Part 2,MCF-7 breast cancer cells and MCF 10A human mammary epithelial cells were metabolically labeled with[~(35)S]sulfate in the presence of individual CEs to observe the CEs' sulfation.Part 3:Five NO Donors with different concentration were added to MCF-7 and MCF10A to analysis the[~(35)S]sulfated estrogen. Moreover,different concentration of TAM,SIN-1(one of the NO Donors) and estrodiol were added to MCF-7 and MCF 10A to evaluate the relationship between TAM and SIN-1 on estrogen sulfation.
RESULTS.Part 1:Among the 145 breast cancer patients,the positive expression of ER and PR was 71.7%and 69.0%,individually;more ER and PR expression was found in postmenopausal breast cancer women compared to patients before menopause,but the result showed no significant difference(P＞0.05).Part 2,Analysis of the labeling media showed the generation and release of exclusively[~(35)S]sulfated 2-methoxy-E_1 or[~(35)S]sulfated 2-or 4-methoxy-E_2 by cells labeled in the presence of 2-OH-E_1 or 2-or 4-OH-E_2.Whereas both [~(35)S]sulfated 4-methoxy-E_1 and[~(35)S]sulfated 4-OH-E_1 were detected in the labeling media of cells labeled in the presence of 4-OH-E_1.These results indicated a concerted action of catechol-O-methyltransferase(COMT) and the cytosolic sulfotransferase(SULT) enzyme(s) in the metabolism of CEs.Enzymatic assays revealed that,five(SULT1A1,SULT1A2, SULT1A3,SULT1C4,and SULT1E1) of eleven known human SULTs tested could use CEs and methoxyestrogens(MEs) as substrates,with SULT1E1 displaying the strongest sulfating activity.Part 2:Five NO Donors can decrease the estrogen sulfation by MCF-7 and MCF 10A cells.There are dose-dependent inhibitory effects between NO Donors and estrogen sulfation. TAM had no significant effects on this inhibition.
CONCLUSION:1,Most breast cancer patients showed ER、PR positive and ER,PR expression showed no difference(P＞0.05) between postmenopausal patients and the patients before menopause.However,there still were breast cancer patients with negative ER.More research should be focused on the breast cancer mechanism except for the ER.2,Sulfation is a major pathway for the biotransformation and excretion of estrogens.The fact that sulfated CEs and MEs were generated and released by cultured cells suggests a concerted action of COMT and SULT enzymes in the metabolism and detoxification of these compounds in vivo.3,The inhibitory effects on estrogens sulfation in MCF-7 and MCF10A cells suggested that the increase of NO might promote the development of breast cancer.TAM showed its therapy effects on breasts cancer could be beyond the inhibition on estrogens sulfation by NO.
引文
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