Hyperleptinemia in obese state renders luminal breast cancers refractory to tamoxifen by coordinating a crosstalk between Med1, miR205 and ErbB.
Hyperleptinemia in obese state renders luminal breast cancers refractory to tamoxifen by coordinating a crosstalk between Med1, miR205 and ErbB.
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DOI：
10.1038/s41523-021-00314-9
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发表时间：
2021-08-13
影响因子：
5.9
通讯作者：
Sharma D
中科院分区：
文献类型：
--
作者：
Nagalingam A;Siddharth S;Parida S;Muniraj N;Avtanski D;Kuppusamy P;Elsey J;Arbiser JL;Győrffy B;Sharma D
患有激素受体阳性乳腺癌的肥胖妇女对治疗反应差，预后差。然而，肥胖/高瘦素血症可能降低激素治疗疗效的潜在分子机制仍然难以捉摸。与非肥胖小鼠相比，患有高瘦素血症的肥胖小鼠表现出肿瘤进展加快，对他莫昔芬的反应较差。外源性瘦素消除他莫昔芬介导的生长抑制，并增强乳腺肿瘤的生长，即使在他莫昔芬的存在。从机制上讲，瘦素诱导磷酸化雌激素受体的核转位，增加雌激素受体应答基因的表达，同时通过消除他莫昔芬诱导的辅阻遏物NCoR、SMRT和Mi2的募集和增强辅激活物结合来减少他莫昔芬介导的基因阻遏。此外，计算机分析显示，共激活因子Med 1可能与48个（74个中的）肥胖特征基因相关。有趣的是，瘦素通过减少miR-205上调Med 1表达，并通过Her 2和EGFR的激活介导的磷酸化增加其功能激活。值得注意的是，Med 1沉默消除了瘦素对他莫昔芬疗效的负面影响。此外，honoklatin或脂联素治疗有效地抑制瘦素诱导的Med 1表达，并提高他莫昔芬在高瘦素血症状态下的疗效。这些研究揭示了肥胖/高瘦素血症状态如何导致对他莫昔芬的不良反应的机制见解，涉及瘦素-miR 205-Med 1和瘦素-Her 2-EGFR-Med 1轴，并提出生物活性化合物honoklatin和脂肪细胞因子脂联素作为可以阻断瘦素对他莫昔芬的负面影响的试剂。
Obese women with hormone receptor-positive breast cancer exhibit poor response to therapy and inferior outcomes. However, the underlying molecular mechanisms by which obesity/hyperleptinemia may reduce the efficacy of hormonal therapy remain elusive. Obese mice with hyperleptinemia exhibit increased tumor progression and respond poorly to tamoxifen compared to non-obese mice. Exogenous leptin abrogates tamoxifen-mediated growth inhibition and potentiates breast tumor growth even in the presence of tamoxifen. Mechanistically, leptin induces nuclear translocation of phosphorylated-ER and increases the expression of ER-responsive genes, while reducing tamoxifen-mediated gene repression by abrogating tamoxifen-induced recruitment of corepressors NCoR, SMRT, and Mi2 and potentiating coactivator binding. Furthermore, in silico analysis revealed that coactivator Med1 potentially associates with 48 (out of 74) obesity-signature genes. Interestingly, leptin upregulates Med1 expression by decreasing miR-205, and increases its functional activation via phosphorylation, which is mediated by activation of Her2 and EGFR. It is important to note that Med1 silencing abrogates the negative effects of leptin on tamoxifen efficacy. In addition, honokiol or adiponectin treatment effectively inhibits leptin-induced Med1 expression and improves tamoxifen efficacy in hyperleptinemic state. These studies uncover the mechanistic insights how obese/hyperleptinemic state may contribute to poor response to tamoxifen implicating leptin-miR205-Med1 and leptin-Her2-EGFR-Med1 axes, and present bioactive compound honokiol and adipocytokine adiponectin as agents that can block leptin’s negative effect on tamoxifen.
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影响因子：
4.8
作者：
Gonzalez-Perez RR;Xu Y;Guo S;Watters A;Zhou W;Leibovich SJ
通讯作者：
Leibovich SJ
影响因子：
11.2
作者：
Chang CC;Wu MJ;Yang JY;Camarillo IG;Chang CJ
通讯作者：
Chang CJ
影响因子：
--
作者：
Avtanski DB;Nagalingam A;Bonner MY;Arbiser JL;Saxena NK;Sharma D
通讯作者：
Sharma D
影响因子：
--
作者：
Avtanski DB;Nagalingam A;Kuppusamy P;Bonner MY;Arbiser JL;Saxena NK;Sharma D
通讯作者：
Sharma D
影响因子：
6.4
作者：
Dal Maso, Luigino;Zucchetto, Antonella;Franceschi, Silvia
通讯作者：
Franceschi, Silvia