Vascular endothelial growth factor receptor 2 and downstream p38 mitogen-activated protein kinase are possible candidate markers of intrinsic resistance to adjuvant endocrine treatment in steroid receptor positive breast cancer
Vascular endothelial growth factor receptor 2 and downstream p38 mitogen-activated protein kinase are possible candidate markers of intrinsic resistance to adjuvant endocrine treatment in steroid receptor positive breast cancer
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DOI：
10.1007/s10549-010-1252-x
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发表时间：
2011-01-01
影响因子：
3.8
通讯作者：
Lehtio, Janne
中科院分区：
文献类型：
--
作者：
Linderholm, Barbro K.;Hellborg, Henrik;Lehtio, Janne
酪氨酸激酶受体和丝裂原活化蛋白激酶（MAPK）之间的串扰被认为与内分泌抵抗有关。我们想研究辅助内分泌治疗（主要是他莫昔芬）2年或5年后，肿瘤内血管内皮生长因子受体2（VEGFR 2）和p38 MAPK水平与无复发（RFS）和乳腺癌校正生存期（BCCS）的关系。我们还想研究这些标记物与早期和晚期复发的关系。VEGFR 2（n = 381）和p38（n = 174）通过酶联免疫吸附测定法测定1993-1996年诊断的原发性BC的肿瘤匀浆。VEGFR 2和p38蛋白质的范围很广，中位数分别为0.72 pg/μ g DNA（范围0.0-11.66）和0.04 pg/μ g DNA（范围0.0-6.79）。p38的可检测水平在65%中登记并被分类为阳性。VEGFR 2水平越高，VEGF（P = 0.005）、p38 MAPK（P = 0.018）、ER阴性（P = 0.008）、肿瘤越大（P = 0.001）、组织病理学分级III（P = 0.018）、远处转移（P = 0.044）、RFS越短（P = 0.013）和BCCS越短（P = 0.017）。p38表达与PgR阴性（P = 0.044）和早期复发（P = 0.021）显著相关，而在后期随访期间无差异（P = 0.73）。较高的VEGFR 2对早期（P = 0.029）和晚期复发（P = 0.018）都有显著的负面影响，而VEGF仅预测晚期复发（P = 0.037）。我们的初步结果表明，较高的肿瘤内VEGFR 2和p38 MAPK作为候选标记物的内在阻力辅助内分泌治疗。
A cross talk between tyrosine kinase receptors and mitogen-activated protein kinases (MAPKs) is proposed as involved in endocrine resistance. We wanted to investigate intratumoral levels of vascular endothelial growth factor receptor 2 (VEGFR2) and p38 MAPK in relation to relapse-free (RFS) and breast cancer corrected survival (BCCS) after adjuvant endocrine treatment, mainly tamoxifen for 2 or 5 years. We also wanted to investigate these markers in relation to early and late recurrences. VEGFR2 (n = 381) and p38 (n = 174) were determined by enzyme-linked immuno-sorbent assays in tumor homogenates from primary BC diagnosed 1993-1996. Wide ranges of VEGFR2 and p38 proteins were found; median 0.72 pg/mu g DNA (range 0.0-11.66), and 0.04 pg/mu g DNA (range 0.0-6.79), respectively. Detectable levels of p38 were registered in 65% and classified positive. Higher VEGFR2 were correlated to higher VEGF (P = 0.005), p38 MAPK (P = 0.018), negative ER (P = 0.008), larger tumors (P = 0.001), histopathological grade III (P = 0.018), distant metastasis (P = 0.044), shorter RFS (P = 0.013), and shorter BCCS (P = 0.017). Expression of p38 was significantly correlated with negative PgR (P = 0.044) and with early relapses (P = 0.021), while no difference was seen during the later follow-up period (P = 0.73). Higher VEGFR2 had a significant negative impact on both early (P = 0.029) and later recurrences (P = 0.018), while VEGF only predicted later relapses (P = 0.037). Our preliminary results suggest higher intratumoral levels of VEGFR2 and p38 MAPK as candidate markers of intrinsic resistance for adjuvant endocrine therapy.