Oestrogen receptor-mediated modulation of the EGFR/MAPK pathway in tamoxifen-resistant MCF-7 cells
Oestrogen receptor-mediated modulation of the EGFR/MAPK pathway in tamoxifen-resistant MCF-7 cells
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DOI：
10.1023/a:1025484908380
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发表时间：
2003-09-01
影响因子：
3.8
通讯作者：
Nicholson, RI
中科院分区：
文献类型：
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作者：
Hutcheson, IR;Knowlden, JM;Nicholson, RI
在临床上，雌激素受体（ER）水平通常在获得他莫昔芬耐药性时维持，然而，肿瘤再生长与表皮生长因子受体（EGFR）的表达增加和丝裂原活化蛋白激酶（MAPK）途径的激活有关。在本研究中，我们使用雌激素受体下调剂氟维司汀（Faslodex）来研究雌激素受体对他莫昔芬耐药（TAM-R）人乳腺癌细胞系生长的影响。在亲本野生型MCF-7 （WT）和TAM-R细胞中，ER mRNA和蛋白的表达水平相当。氟维司汀消除了内质网蛋白的表达并抑制了两种细胞系的增殖。氟维西汀的生长抑制作用与TAM-R细胞中基础EGFR、c-erbB2和ERK1/2活性的降低有关，但与WT细胞无关。雌激素反应元件(ERE)-荧光素酶报告活性测定的ER功能和PgR、pS2和转化生长因子α (TGFalpha)的表达在TAM-R细胞中与WT细胞相比显著降低，并且在两种细胞系中氟维司汀处理后进一步降低。表皮生长因子（EGF）和TGFa显著增加了两种细胞系中EGFR/MAPK通路的活性。配体诱导的EGFR/MAPK激活在氟维司汀不存在和不存在的情况下都能促进TAM-R细胞的生长，而在相同条件下，在WT细胞中没有观察到增殖活性。这些结果表明，内质网可能通过调节TGFa可用性来调节TAM-R细胞中EGFR/MAPK的信号传导效率。这种影响可以通过外源性EGFR配体的作用来克服，外源性EGFR配体可以增强EGFR/MAPK信号活性，从而产生内分泌不敏感的细胞生长。
Oestrogen receptor (ER) levels are usually maintained on acquisition of tamoxifen resistance in the clinic, however, tumour re-growth is associated with increased expression of epidermal growth factor receptor ( EGFR) and activation of the mitogen activated protein kinase ( MAPK) pathway. In the present study we have used the ER down-regulator fulvestrant ('Faslodex') to investigate the influence of the ER on growth of a tamoxifen-resistant (TAM-R) human breast cancer cell line. Expression levels of ER mRNA and protein were equivalent in parental wild-type MCF-7 (WT) and TAM-R cells. Fulvestrant eliminated ER protein expression and inhibited proliferation in both cell lines. The growth inhibitory effects of fulvestrant were associated with a decrease in basal EGFR, c-erbB2 and ERK1/2 activity in TAM-R but not WT cells. ER functionality as determined by oestrogen response element ( ERE)-luciferase reporter activity and expression of PgR, pS2 and transforming growth factor alpha (TGFalpha) was significantly reduced in TAM-R compared to WT cells and was further decreased by fulvestrant treatment in both cell lines. Epidermal growth factor (EGF) and TGFa significantly increased EGFR/MAPK pathway activity in both cell lines. Ligand-induced EGFR/MAPK activation promoted TAM-R cell growth in both the absence and presence of fulvestrant, whereas no proliferative activity was observed under the same conditions in WT cells. These results suggest that the ER modulates EGFR/MAPK signalling efficiency in TAM-R cells possibly through the regulation of TGFa availability. This effect may be overcome by the action of exogenous EGFR ligands, which strengthen EGFR/MAPK signalling activity to generate endocrine-insensitive cell growth.