GPR30 as an initiator of tamoxifen resistance in hormone-dependent breast cancer.
GPR30 as an initiator of tamoxifen resistance in hormone-dependent breast cancer.
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GPR30 作为激素依赖性乳腺癌他莫昔芬耐药的引发剂。
DOI：
10.1186/bcr3581
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发表时间：
2013-11-29
期刊：
影响因子：
--
通讯作者：
Yang G
中科院分区：
文献类型：
--
作者：
Mo Z;Liu M;Yang F;Luo H;Li Z;Tu G;Yang G
他莫昔芬被广泛用于治疗激素依赖型乳腺癌，但其治疗效果受到耐药性发展的限制。在这里，我们研究了雌激素G蛋白偶联受体30(GPR30)在乳腺癌三苯氧胺耐药中的作用。采用免疫组织化学方法检测GPR30和表皮生长因子受体(EGFR)在乳腺癌原发灶和相应转移灶中的表达。采用四甲基偶氮唑盐(MTT法)、免疫印迹、RT-PCR、免疫荧光、酶联免疫吸附试验和流式细胞仪等方法，研究GPR30在三苯氧胺耐药细胞亚克隆形成中的作用。采用肿瘤体积测量和末端脱氧核苷酸转移酶缺口末端标记法(TUNEL)评价GPR30拮抗剂G15联合4-羟基他莫昔芬()对-R裸鼠移植瘤的抗肿瘤作用。在53例乳腺癌标本中，GPR30在MTS中的表达高于匹配的PTS；在MTS中，GPR30和EGFR的表达模式密切相关。与亲本细胞相比，-R细胞对17β-雌二醇(E2)、GPR30激动剂G1和有更强的生长反应，并显著增强丝裂原活化蛋白(MAP)激酶的激活，但这种增强的活性被G15或AG1478所抵消。在-R细胞中，GPR30细胞表面易位促进了与表皮生长因子受体的串扰，并减少了cAMP的产生，减弱了对表皮生长因子受体信号的抑制。联合治疗既能促进-R细胞的凋亡，又能减缓耐药肿瘤的进展。长期的内分泌治疗促进GPR30转位到细胞表面，这干扰了EGFR信号通路；GPR30也减弱了对MAP激酶的抑制。这些因素导致乳腺癌患者对他莫昔芬产生耐药性。GPR30抑制剂和他莫昔芬的联合治疗可能为耐药乳腺癌提供一种新的治疗选择。
Tamoxifen is widely used to treat hormone-dependent breast cancer, but its therapeutic benefit is limited by the development of drug resistance. Here, we investigated the role of estrogen G-protein coupled receptor 30 (GPR30) on Tamoxifen resistance in breast cancer. Primary tumors (PTs) of breast cancer and corresponding metastases (MTs) were used to evaluate the expression of GPR30 and epidermal growth factor receptor (EGFR) immunohistochemically. Tamoxifen-resistant (TAM-R) subclones derived from parent MCF-7 cells were used to investigate the role of GPR30 in the development of tamoxifen resistance, using MTT assay, western blot, RT-PCR, immunofluorescence, ELISA and flow cytometry. TAM-R xenografts were established to assess anti-tumor effects of combination therapy with GPR30 antagonist G15 plus 4-hydroxytamoxifen (Tam), using tumor volume measurement and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). In 53 human breast cancer specimens, GPR30 expression in MTs increased compared to matched PTs; in MTs, the expression patterns of GPR30 and EGFR were closely related. Compared to parent MCF-7 cells, TAM-R cells had greater growth responses to 17β-estradiol (E2), GPR30 agonist G1 and Tam, and significantly higher activation of Mitogen-activated protein (MAP) kinases; but this increased activity was abolished by G15 or AG1478. In TAM-R cells, GPR30 cell-surface translocation facilitated crosstalk with EGFR, and reduced cAMP generation, attenuating inhibition of EGFR signaling. Combination therapy both promoted apoptosis in TAM-R cells and decreased drug-resistant tumor progression. Long-term endocrine treatment facilitates the translocation of GPR30 to cell surfaces, which interferes with the EGFR signaling pathway; GPR30 also attenuates the inhibition of MAP kinases. These factors contribute to tamoxifen resistance development in breast cancer. Combination therapy with GPR30 inhibitors and tamoxifen may provide a new therapeutic option for drug-resistant breast cancer.
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影响因子：
3.8
作者：
Arias-Pulido, Hugo;Royce, Melanie;Gong, Yun;Joste, Nancy;Lomo, Lesley;Lee, Sang-Joon;Chaher, Nabila;Verschraegen, Claire;Lara, Juanita;Prossnitz, Eric R.;Cristofanilli, Massimo
通讯作者：
Cristofanilli, Massimo
影响因子：
11.2
作者：
Ariazi EA;Brailoiu E;Yerrum S;Shupp HA;Slifker MJ;Cunliffe HE;Black MA;Donato AL;Arterburn JB;Oprea TI;Prossnitz ER;Dun NJ;Jordan VC
通讯作者：
Jordan VC
影响因子：
45.3
作者：
Delozier, T;Spielmann, M;Namer, M
通讯作者：
Namer, M
影响因子：
3.8
作者：
Dihge, Looket;Bendahl, Par-Ola;Ferno, Marten
通讯作者：
Ferno, Marten
DOI：
10.1016/s0960-0760(01)00190-x
发表时间：
2002-02-01
影响因子：
4.1
作者：
Filardo, EJ
通讯作者：
Filardo, EJ