Inhibition of N-methyl-N-nitrosourea- and 7,12-dimethylbenz[a] anthracene-induced rat mammary tumorigenesis by dietary cholesterol is independent of Ha-Ras mutations.
Inhibition of N-methyl-N-nitrosourea- and 7,12-dimethylbenz[a] anthracene-induced rat mammary tumorigenesis by dietary cholesterol is independent of Ha-Ras mutations.
复制标题
膳食胆固醇对 N-甲基-N-亚硝基脲和 7,12-二甲基苯并[a]蒽诱导的大鼠乳腺肿瘤发生的抑制作用与 Ha-Ras 突变无关。
作者：
A. El;Michael C. Archer
膳食胆固醇以前已被证明可以抑制大鼠乳腺肿瘤的发生，但其机制尚不清楚。组织对血清低密度脂蛋白胆固醇的摄取导致3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶下调，HMG-CoA还原酶是胆固醇生物合成中催化甲羟戊酸形成的限速酶。除了作为胆固醇的前体，甲羟戊酸是DNA合成和细胞增殖所必需的。类异戊二烯，也来自甲羟戊酸，是翻译后修饰Ras蛋白所必需的，Ras蛋白在许多致癌物诱导的大鼠乳腺肿瘤中发生突变。因此，本研究的目的是确定胆固醇对肿瘤发生的抑制是否依赖于Ha-ras基因突变的频率。雌性Sprague-Dawley大鼠（30只/组）给予单剂量的N-甲基-N-亚硝基脲（MNU，50 mg/kg i. p.）或7，12-二甲基苯并[a]蒽（DMBA，100 mg/kg灌胃），这些致癌物分别产生在密码子12或61中具有高（MNU）或低（DMBA）频率Ha-ras突变的肿瘤。大鼠喂食对照AIN-93 G饮食或补充有0.3%胆固醇的对照饮食14周。膳食胆固醇显著降低了DMBA组（83对100%，P < 0.05）或MNU组（53对77%，P < 0.05）大鼠的最终肿瘤发生率。HMG-CoA还原酶活性在乳腺肿瘤中高于正常乳腺，但该酶的活性仅在乳腺中而不是在肿瘤中通过胆固醇喂养而降低。在对照组（65%）和胆固醇喂养组（68%）中，MNU诱导的肿瘤中Ha-ras突变频率很高。由DMBA诱导的肿瘤具有低频率的Ha-ras突变，在对照组（21%）和胆固醇喂养组（18%）之间也没有差异。这些研究结果表明，膳食胆固醇抑制乳腺肿瘤的发生诱导的MNU或DMBA和抑制是独立的类型或程度的突变的Ha-ras基因。
Dietary cholesterol has previously been shown to inhibit rat mammary tumorigenesis but the mechanisms remain unclear. Uptake of serum low density lipoprotein cholesterol by tissues leads to down-regulation of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, the rate limiting enzyme in cholesterol biosynthesis that catalyzes the formation of mevalonate. In addition to being a precursor of cholesterol, mevalonate is necessary for DNA synthesis and cell proliferation. Isoprenoids, also derived from mevalonate, are required for the post-translational modification of Ras proteins that are mutated in a number of carcinogen-induced rat mammary tumors. The purpose of this study, therefore, was to determine whether inhibition of tumorigenesis by cholesterol is dependent on the frequency of mutations in the Ha-ras gene. Female Sprague-Dawley rats (30/group) were given a single dose of either N-methyl-N-nitrosourea (MNU, 50 mg/kg i.p.) or 7, 12-dimethylbenz[a]anthracene (DMBA, 100 mg/kg intragastrally), carcinogens that produce tumors with either a high (MNU) or low (DMBA) frequency of Ha-ras mutations in codon 12 or 61, respectively. Rats were fed either a control AIN-93G diet or the control diet supplemented with 0.3% cholesterol for 14 weeks. Dietary cholesterol significantly decreased the final tumor incidence in rats given DMBA (83 versus 100%, P < 0.05) or MNU (53 versus 77%, P < 0.05). HMG-CoA reductase activity was higher in mammary tumors than in normal mammary glands, but the activity of this enzyme was reduced by cholesterol feeding only in mammary glands and not in tumors. Tumors induced by MNU had a high frequency of Ha-ras mutations in both the control (65%) and cholesterol-fed (68%) groups. Tumors induced by DMBA had a low frequency of Ha-ras mutations that also did not differ between the control (21%) and cholesterol-fed (18%) groups. These findings show that dietary cholesterol inhibits mammary tumorigenesis induced by either MNU or DMBA and that the inhibition is independent of the type or extent of mutations in the Ha-ras gene.
登录
查看更多内容
影响因子：
11.2
作者：
Joyce Bos
通讯作者：
Joyce Bos
影响因子：
56.9
作者：
BROWN, MS;GOLDSTEIN, JL
通讯作者：
GOLDSTEIN, JL
ras/胆固醇的联系：对 ras 致癌性的影响。
影响因子：
--
作者：
Cox,AD;Der,CJ
通讯作者：
Der,CJ
直接原位转移 v-Ha-ras 后柠檬烯对乳腺癌诱导的化学预防。
影响因子：
11.2
作者：
Gould,MN;Moore,CJ;Zhang,R;Wang,B;Kennan,WS;Haag,JD
通讯作者：
Haag,JD
影响因子：
8
作者：
R. Kumar;M. Barbacid
通讯作者：
R. Kumar;M. Barbacid