Targeting tyrosine-kinases and estrogen receptor abrogates resistance to endocrine therapy in breast cancer.
Targeting tyrosine-kinases and estrogen receptor abrogates resistance to endocrine therapy in breast cancer.
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DOI：
10.18632/oncotarget.2022
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发表时间：
2014-10-15
期刊：
影响因子：
--
通讯作者：
González-Angulo AM
中科院分区：
文献类型：
--
作者：
Liu S;Meng X;Chen H;Liu W;Miller T;Murph M;Lu Y;Zhang F;Gagea M;Arteaga CL;Mills GB;Meric-Bernstam F;González-Angulo AM
尽管有许多治疗方法可以有效地抑制乳腺癌中的雌激素信号，但仍有很大一部分雌激素受体（ER）阳性的恶性肿瘤患者会死于疾病。本研究表明，雌激素受体阳性乳腺癌细胞的长期雌激素剥夺（LTED）治疗导致雌激素受体表达的适应性增加和随后多种酪氨酸激酶的激活。内质网下调剂氟维司汀和宽激酶抑制剂达沙替尼联合治疗，通过减少细胞增殖、细胞存活、细胞侵袭和乳腺腺泡形成，对LTED细胞表现出协同作用。利用蛋白质阵列和功能蛋白质组学分析筛选激酶磷酸化表明，氟维司汀和达沙替尼联合使用可抑制ltted细胞中组成性激活的多种酪氨酸激酶和癌症相关途径。由于ltd细胞显示胰岛素受体(InsR)/胰岛素样生长因子1受体（IGF-1R）信号传导增加，我们在与氟维司汀和达沙替尼联合使用时添加了抗igf -1抗体，以进一步增强抑制作用。然而，在单层培养中，加入MK0646仅适度增加了细胞生长的抑制作用，但没有抑制腺泡的形成，也没有抑制细胞在体外的迁移和体内的侵袭。因此，联合使用氟维司汀和达沙替尼，而不是MK0646，可能对酪氨酸激酶激活的内分泌治疗耐药乳腺癌患者有益。
Despite numerous therapies that effectively inhibit estrogen signaling in breast cancer, a significant proportion of patients with estrogen receptor (ER)-positive malignancy will succumb to their disease. Herein we demonstrate that long-term estrogen deprivation (LTED) therapy among ER-positive breast cancer cells results in the adaptive increase in ER expression and subsequent activation of multiple tyrosine kinases. Combination therapy with the ER down-regulator fulvestrant and dasatinib, a broad kinase inhibitor, exhibits synergistic activity against LTED cells, by reduction of cell proliferation, cell survival, cell invasion and mammary acinar formation. Screening kinase phosphorylation using protein arrays and functional proteomic analysis demonstrates that the combination of fulvestrant and dasatinib inhibits multiple tyrosine kinases and cancer-related pathways that are constitutively activated in LTED cells. Because LTED cells display increased insulin receptor (InsR)/insulin-like growth factor 1 receptor (IGF-1R) signaling, we added an ant-IGF-1 antibody to the combination with fulvestrant and dasatinib in an effort to further increase the inhibition. However, adding MK0646 only modestly increased the inhibition of cell growth in monolayer culture, but neither suppressed acinar formation nor inhibited cell migration in vitro and invasion in vivo. Therefore, combinations of fulvestrant and dasatinib, but not MK0646, may benefit patients with tyrosine-kinase-activated, endocrine therapy-resistant breast cancer.
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影响因子：
11.5
作者：
Atzori, Francesco;Tabernero, Josep;Baselga, Jose
通讯作者：
Baselga, Jose
影响因子：
11.5
作者：
Carlos Montero, Juan;Seoane, Samuel;Pandiella, Atanasio
通讯作者：
Pandiella, Atanasio
影响因子：
4.8
作者：
Liu, SY;Yu, SX;Fang, XJ
通讯作者：
Fang, XJ
影响因子：
45.3
作者：
Dowsett, Mitch;Cuzick, Jack;Peto, Richard
通讯作者：
Peto, Richard
影响因子：
4.8
作者：
Knowlden, JM;Hutcheson, IR;Nicholson, RI
通讯作者：
Nicholson, RI