Stress hormones reduce the efficacy of paclitaxel in triple negative breast cancer through induction of DNA damage.
Stress hormones reduce the efficacy of paclitaxel in triple negative breast cancer through induction of DNA damage.
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DOI：
10.1038/bjc.2015.133
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发表时间：
2015-04-28
影响因子：
8.8
通讯作者：
Flint, M. S.
中科院分区：
文献类型：
--
作者：
Reeder, A.;Attar, M.;Nazario, L.;Bathula, C.;Zhang, A.;Hochbaum, D.;Roy, E.;Cooper, K. L.;Oesterreich, S.;Davidson, N. E.;Neumann, C. A.;Flint, M. S.
应激激素影响三阴性乳腺癌（TNBC）病因和治疗的机制尚不清楚。我们以前已经表明，应激激素，皮质醇和儿茶酚胺诱导快速DNA损伤和影响NIH 3T3成纤维细胞的DNA修复。这项研究调查了应激激素是否会增加乳腺癌细胞的DNA损伤，以及这是否会影响药物疗效。我们首先筛选了一组39个乳腺癌细胞系的肾上腺素能和糖皮质激素受体的表达，并检查是否应激激素诱导DNA损伤和改变细胞周期调控体外。TNBC异种移植模型用于评估束缚应激对肿瘤生长和对紫杉醇的化学敏感性的影响。我们发现，应激激素诱导DNA损伤，ATR磷酸化，这是伴随着G1细胞激酶抑制剂p21的上调和细胞周期停止在G1期的TNBC。p21基因敲除可消除应激激素引起的G1期阻滞。我们还证明，压力显着降低紫杉醇的疗效。我们描述了一种新的机制，通过这种机制，应激激素可以诱导对紫杉醇的耐药性，这可能对治疗TNBC患者的耐药性具有深远的意义。
The mechanisms by which stress hormones impact triple-negative breast cancer (TNBC) etiology and treatment are unclear. We have previously shown that stress hormones, cortisol, and catecholamines induce rapid DNA damage and impact DNA repair in NIH 3T3 fibroblasts. This study investigates whether stress hormones increase DNA damage in breast cancer cells and if this impacts drug efficacy. We first screened a panel of 39 breast cancer cell lines for expression of adrenergic and glucocorticoid receptors and examined if stress hormones induce DNA damage and alter cell cycle regulation in vitro. A TNBC xenograft model was used to assess the impact of restraint stress on tumour growth and chemosensitivity to paclitaxel. We found that stress hormones induced DNA damage, phosphorylation of ATR, which was accompanied by an up-regulation of the G1 cell kinase inhibitor p21 and a cell cycle halt of TNBCs in the G1 phase. p21 knockdown abrogated G1 arrest by stress hormones. We also demonstrated that stress significantly decreased efficacy of paclitaxel. We describe a novel mechanism through which stress hormones can induce drug resistance to paclitaxel, which may have profound implications for treating drug resistance in patients with TNBC.
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影响因子：
3.7
作者：
Flint, Melanie S.;Kim, Grace;Conrads, Thomas P.
通讯作者：
Conrads, Thomas P.
影响因子：
39.2
作者：
Nelson HD;Zakher B;Cantor A;Fu R;Griffin J;O'Meara ES;Buist DS;Kerlikowske K;van Ravesteyn NT;Trentham-Dietz A;Mandelblatt JS;Miglioretti DL
通讯作者：
Miglioretti DL
DOI：
10.3109/10253890.2012.686075
发表时间：
2013-01
期刊：
Stress (Amsterdam, Netherlands)
影响因子：
--
作者：
Flint MS;Baum A;Episcopo B;Knickelbein KZ;Liegey Dougall AJ;Chambers WH;Jenkins FJ
通讯作者：
Jenkins FJ
影响因子：
15.1
作者：
Madden, Kelley S.;Szpunar, Mercedes J.;Brown, Edward B.
通讯作者：
Brown, Edward B.
影响因子：
4.3
作者：
Hara, Makoto R.;Sachs, Benjamin D.;Lefkowitz, Robert J.
通讯作者：
Lefkowitz, Robert J.