Breast cancer growth prevention by statins
Breast cancer growth prevention by statins
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DOI：
10.1158/0008-5472.can-05-4061
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发表时间：
2006-09-01
期刊：
影响因子：
11.2
通讯作者：
Benz, Christopher C.
中科院分区：
文献类型：
--
作者：
Campbell, Michael J.;Esserman, Laura J.;Benz, Christopher C.
他汀类药物是具有多效活性的降胆固醇药物，包括抑制异戊二烯化反应和减少驱动细胞增殖和存活反应的信号。本研究的目的是检查他汀类药物对乳腺癌细胞的影响，在体外和体内，并开始，以确定其作用机制。我们评估了他汀类药物对乳腺癌细胞生长、磷蛋白信号中间体、存活/凋亡调节因子、细胞周期调节因子和活化转录因子的影响。我们还研究了他汀类药物在小鼠ErbB（2+）乳腺癌模型中的体内作用。只有亲脂性他汀类药物在体外具有直接的抗癌活性。Ras或ErbB 2通路激活的乳腺癌细胞似乎比雌激素受体过表达的乳腺癌细胞更敏感，这与内源性活化核因子κ B（NF-κ B）水平相关。通过NF-κ B活化调节细胞存活的关键中间体，以及通过丝裂原活化蛋白激酶级联调节细胞增殖，是受他汀类药物治疗影响的最早的磷蛋白。这些早期效应之后是激活蛋白-1和NF-κ B激活的下降以及其他增殖和凋亡介质的一致变化。体内结果表明，口服他汀类药物可显著抑制小鼠乳腺癌的生长。亲脂性他汀类药物可通过减少易感乳腺癌表型中的增殖和存活信号发挥直接的体外抗癌活性。使用临床相关的他汀类药物剂量在体内抑制肿瘤生长似乎也与降低的肿瘤细胞增殖和存活相关。这些发现为将来在乳腺癌患者中进行他汀类药物试验提供了支持依据。
Statins are cholesterol-lowering drugs with pleiotropic activities including inhibition of isoprenylation reactions and reduction of signals driving cell proliferation and survival responses. The objectives of this study were to examine the effects of statins on breast cancer cells, both in vitro and in vivo, and to begin to determine their mechanism of action. We evaluated the effects of statins on breast cancer cell growth, phosphoprotein signaling intermediates, survival/apoptosis regulators, cell cycle regulators, and activated transcription factors. We also examined the in vivo effect of statin administration in a mouse ErbB(2+) breast cancer model. Only lipophilic statins had direct anticancer activity in vitro. Breast cancer cells with activated Ras or ErbB2 pathways seemed to be more sensitive than those overexpressing estrogen receptor, and this correlated with endogenous levels of activated nuclear factor kappa B (NF-kappa B). Key intermediates regulating cell survival by NF-kappa B activation, as well as cell proliferation by the mitogen activated protein kinase cascade, were among the earliest phosphoproteins influenced by statin treatment. These early effects were followed by declines in activator protein-1 and NF-kappa B activation and concordant changes in other mediators of proliferation and apoptosis. In vivo results showed that oral dosing of statins significantly inhibited the growth of a mouse mammary carcinoma. Lipophilic statins can exert direct anticancer activity in vitro by reducing proliferation and survival signals in susceptible breast cancer phenotypes. Tumor growth inhibition in vivo using a clinically relevant statin dose also seems to be associated with reduced tumor cell proliferation and survival. These findings provide supporting rationale for future statin trials in breast cancer patients.