EGFRvIII-induced estrogen-independence, tamoxifen-resistance phenotype correlates with PgR expression and modulation of apoptotic molecules in breast cancer.
EGFRvIII-induced estrogen-independence, tamoxifen-resistance phenotype correlates with PgR expression and modulation of apoptotic molecules in breast cancer.
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DOI：
10.1002/ijc.24540
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发表时间：
2009-11-01
影响因子：
6.4
通讯作者：
Tang, Careen
中科院分区：
文献类型：
--
作者：
Zhang, Yang;Su, Hua;Rahimi, Massod;Tochihara, Ryan;Tang, Careen
肿瘤特异性、不依赖配体、持续活跃的表皮生长因子受体 (EGFR) 变体 EGFRvIII 在乳腺癌中的研究仍未充分。在此，我们报告，与 MDA-MB-361/wt 细胞相比，ErbB-2 过表达、雌激素依赖性 MDA-MB-361 乳腺癌细胞系中 EGFRvIII 的表达导致去卵巢、无胸腺裸鼠中显着的雌激素非依赖性肿瘤生长。 MDA-MB-361/vIII乳腺癌细胞维持雌激素诱导的肿瘤生长，但在雌激素存在下对他莫昔芬产生耐药性，而MDA-MB-361/wt细胞在雌激素和他莫昔芬存在下肿瘤生长显着减少。单独使用他莫昔芬对 EGFRvIII 介导的不依赖雌激素的肿瘤生长没有显着影响。来自 EGFRvIII 受体的组成型信号传导导致 Akt 和 MAPK 途径的激活增加。雌激素依赖性、他莫昔芬敏感的 MCF-7/vIII 乳腺癌细胞的 ERα 水平不变，但与 MCF-7/wt 细胞相比，孕酮受体 (PgR) 增加。与 MDA-MB-361/wt 细胞相比，MDA-MB-361/vIII 细胞的 ERα 表达减少，孕酮受体 (PgR) 减少更明显。 EGFRvIII 表达也与侵袭性人类乳腺癌样本中 PgR 蛋白的缺失显着相关。在 EGFRvIII 转染子中观察到促凋亡蛋白和抗凋亡蛋白的改变。总之，通过 EGFRvIII 及其下游效应蛋白的组成性信号传导与 ERα 通路交叉，导致 PgR 表达丧失和细胞凋亡通路改变，这可能导致表达 EGFRvIII 的乳腺癌细胞产生雌激素非依赖性、他莫昔芬耐药表型。
The tumor specific, ligand-independent, constitutively active Epidermal Growth Factor Receptor (EGFR) variant, EGFRvIII, remains understudied in breast cancer. Here, we report that expression of EGFRvIII in the ErbB-2-overexpressing, estrogen-dependent MDA-MB-361 breast cancer cell line resulted in significant estrogen-independent tumor growth in ovariectomized, athymic nude mice in comparison to MDA-MB-361/wt cells. MDA-MB-361/vIII breast cancer cells maintained estrogen-induced tumor growth, but were tamoxifen-resistant in the presence of estrogen, while MDA-MB-361/wt cells had a significant reduction in tumor growth in the presence of estrogen and tamoxifen. Tamoxifen alone did not have a significant effect on EGFRvIII-mediated estrogen-independent tumor growth. Constitutive signaling from the EGFRvIII receptor resulted in increased activation of both the Akt and MAPK pathways. Compared to estrogen-dependent, tamoxifen-sensitive MCF-7/vIII breast cancer cells, which had unchanged levels of ERα, but an increase in progesterone receptor (PgR) in comparison to MCF-7/wt cells, MDA-MB-361/vIII cells had a reduction in ERα expression as well as a more pronounced reduction in progesterone receptor (PgR) compared to MDA-MB-361/wt cells. EGFRvIII expression was also significantly associated with an absence of PgR protein in invasive human breast cancer specimens. Alterations of pro-apoptotic proteins and anti-apoptotic proteins were observed in EGFRvIII transfectants. In conclusion, constitutive signaling through EGFRvIII and its down-stream effector proteins crosstalks with the ERα pathway, resulting in loss of PgR expression and alterations in the apoptotic pathway which may result in the estrogen-independent, tamoxifen-resistant phenotype conferred to EGFRvIII-expressing breast cancer cells.
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影响因子：
--
作者：
Cui, XJ;Zhang, P;Lee, AV
通讯作者：
Lee, AV
影响因子：
6.4
作者：
Ge, H;Gong, XQ;Tang, CK
通讯作者：
Tang, CK
影响因子：
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作者：
Antonyak, MA;Moscatello, DK;Wong, AJ
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Wong, AJ
影响因子：
11.5
作者：
Bayliss, Jill;Hilger, Amy;El Ashry, Dorraya
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El Ashry, Dorraya
影响因子：
10.3
作者：
Arpino, G;Weiss, H;Elledge, RM
通讯作者：
Elledge, RM