Oxidative stress contributes to the tamoxifen-induced killing of breast cancer cells: implications for tamoxifen therapy and resistance.
Oxidative stress contributes to the tamoxifen-induced killing of breast cancer cells: implications for tamoxifen therapy and resistance.
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DOI：
10.1038/srep21164
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发表时间：
2016-02-17
影响因子：
4.6
通讯作者：
Brindley DN
中科院分区：
文献类型：
--
作者：
Bekele RT;Venkatraman G;Liu RZ;Tang X;Mi S;Benesch MG;Mackey JR;Godbout R;Curtis JM;McMullen TP;Brindley DN
他莫昔芬是雌激素受体-α（ERα）阳性乳腺癌患者的公认治疗方法。然而，对他莫昔芬的临床耐药，如治疗中的复发或进展所证明的，是常见的，并且在转移导致死亡之前。为了改善乳腺癌治疗，了解导致他莫昔芬耐药的机制至关重要。这项研究表明，在患者肿瘤中积累的他莫昔芬及其代谢产物的浓度可以杀死ERα阳性和ERα阴性乳腺癌细胞。这依赖于氧化损伤和抗氧化剂将癌细胞从他莫昔芬诱导的凋亡中拯救出来。乳腺癌细胞通过增加Nrf 2表达并随后激活抗氧化反应元件（ARE）来对他莫昔芬诱导的氧化做出反应。这增加了抗氧化基因和多药耐药转运蛋白的转录。因此，乳腺癌细胞能够破坏或输出有毒的氧化产物，从而增加他莫昔芬诱导的氧化损伤的存活率。癌细胞中的这些反应也发生在他莫昔芬治疗小鼠的乳腺肿瘤中。此外，Nrf 2、ABCC 1、ABCC 3和NAD（P）H脱氢酶醌-1在诊断时乳腺肿瘤患者中的高水平表达预示着他莫昔芬治疗后生存率差。因此，克服他莫昔芬诱导的ARE激活可以增加他莫昔芬治疗乳腺癌的疗效。
Tamoxifen is the accepted therapy for patients with estrogen receptor-α (ERα)-positive breast cancer. However, clinical resistance to tamoxifen, as demonstrated by recurrence or progression on therapy, is frequent and precedes death from metastases. To improve breast cancer treatment it is vital to understand the mechanisms that result in tamoxifen resistance. This study shows that concentrations of tamoxifen and its metabolites, which accumulate in tumors of patients, killed both ERα-positive and ERα-negative breast cancer cells. This depended on oxidative damage and anti-oxidants rescued the cancer cells from tamoxifen-induced apoptosis. Breast cancer cells responded to tamoxifen-induced oxidation by increasing Nrf2 expression and subsequent activation of the anti-oxidant response element (ARE). This increased the transcription of anti-oxidant genes and multidrug resistance transporters. As a result, breast cancer cells are able to destroy or export toxic oxidation products leading to increased survival from tamoxifen-induced oxidative damage. These responses in cancer cells also occur in breast tumors of tamoxifen-treated mice. Additionally, high levels of expression of Nrf2, ABCC1, ABCC3 plus NAD(P)H dehydrogenase quinone-1 in breast tumors of patients at the time of diagnosis were prognostic of poor survival after tamoxifen therapy. Therefore, overcoming tamoxifen-induced activation of the ARE could increase the efficacy of tamoxifen in treating breast cancer.