Molecular changes in tamoxifen-resistant breast cancer: Relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase
Molecular changes in tamoxifen-resistant breast cancer: Relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase
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DOI：
10.1200/jco.2005.01.172
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发表时间：
2005-04-10
影响因子：
45.3
通讯作者：
Dowsett, M
中科院分区：
文献类型：
--
作者：
Gutierrez, MC;Detre, S;Dowsett, M
为了评估在配对的临床乳腺癌标本和异种移植模型中，在他莫昔芬治疗前和肿瘤进展时，生长因子受体与雌激素受体（ER）的相互作用作为他莫昔芬耐药的可能机制。和磷酸化（p）p38促分裂原活化蛋白激酶（MAPK）、p-ERK 1/2 MAPK和p-Akt。三苯氧胺耐药前和耐药后的异种移植MCF-7肿瘤p-p38水平进行了评估。结果治疗前，ER，PgR和Bcl-2之间有很强的相关性，ER和HER-2之间呈负相关。这些相关性在他莫昔芬耐药肿瘤中消失，取而代之的是ER与p-p38和p-ERK之间的强相关性。ER表达在17%的耐药肿瘤中丢失。26例HER-2阴性的肿瘤中有3例（11%）在耐药时扩增和/或过表达。所有ER阳性肿瘤，过度表达HER-2最初或在电阻表达高水平的p-p38。在预处理和他莫昔芬耐药标本中，p-p38和p-ERK之间存在很强的相关性。与临床样本一样，在他莫昔芬耐药的异种移植肿瘤中，p-p38显着增加。结论随着肿瘤的进展，驱动肿瘤生长的分子途径可能会发生变化。ER、HER-2、p38和ERK之间的相互作用可能导致他莫昔芬耐药性，并可能提供克服这种耐药性的分子靶点。
PurposeTo evaluate growth factor receptor cross talk with the estrogen receptor (ER) in paired clinical breast cancer specimens and in a xenograft model before tamoxifen and at tumor progression as a possible mechanism for tamoxifen resistance.MethodsSpecimen pairs from 39 patients were tissue arrayed and stained for ER, progesterone receptor (PgR), Bcl-2, c-ErbB2 (HER-2), and phosphorylated (p) p38 mitogen-activated protein kinase (MAPK), p-ERK1/2 MAPK, and p-Akt. Xenograft MCF-7 tumors before and after tamoxifen resistance were assessed for levels of p-p38.ResultsPretreatment, there were strong correlations between ER, PgR, and Bcl-2, and an inverse correlation between ER and HER-2. These correlations were lost in the tamoxifen-resistant tumors and replaced by strong correlations between ER and p-p38 and p-ERK. ER expression was lost in 17% of resistant tumors. Three (11%) of the 26 tumors originally negative for HER-2 became amplified and/or overexpressed at resistance. All ER-positive tumors that overexpressed HER-2 originally or at resistance expressed high levels of p-p38. In the pretreatment and tamoxifen-resistant specimens, there were strong correlations between p-p38 and p-ERK. In the tamoxifen-resistant xenograft tumors, like the clinical samples, there was a striking increase in p-p38.ConclusionThe molecular pathways driving tumor growth can change as the tumor progresses. Crosstalk between ER, HER-2, p38, and ERK may contribute to tamoxifen resistance and may provide molecular targets to overcome this resistance.