Estrogen receptor-associated expression of keratinocyte growth factor and its possible role in the inhibition of apoptosis in human breast cancer
Estrogen receptor-associated expression of keratinocyte growth factor and its possible role in the inhibition of apoptosis in human breast cancer
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DOI：
10.1038/labinvest.3700166
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发表时间：
2004-11-01
影响因子：
5
通讯作者：
Koji, T
中科院分区：
文献类型：
--
作者：
Tamaru, N;Hishikawa, Y;Koji, T
虽然已知雌激素在乳腺癌的发病机制中起关键作用，但雌激素作用的分子机制仍不清楚。在本研究中，角质形成细胞生长因子(KGF)及其受体(KGFR)作为一种生长因子介导雌激素作用，在乳腺癌的发病机制中起着重要的作用，因为KGF在多种类固醇激素依赖的组织中都有重要的作用。首先，我们使用42例乳腺癌患者的石蜡包埋标本，用新产生的抗体进行免疫组织化学和T-T二聚体合成寡核苷酸探针的非放射性原位杂交，检测KGF和KGFR的表达模式。接下来，我们将结果与雌激素受体(ER)α和β的表达、增殖活性和细胞凋亡率(TUNEL染色)进行比较。此外，采用类似的方法分析了KGF在ER阳性(MCF7，ZR-75-1)和ER阴性(SK-BR-3，MDA-MB-231)人乳腺癌细胞系中的表达和作用。在手术标本中，KGF在癌细胞和间质细胞中表达19例(45%)，KGFR在癌细胞中表达24例(57%)。KGF和KGFR表达分析中蛋白质和mRNA的分布基本一致。此外，KGF的表达与ER a的表达密切相关，KGF和KGFR的共同表达与较低的TUNEL指数显著相关，而与细胞增殖活性无关。与体内研究结果一致，KGF在体外仅在ERα阳性的MCF7和ZR-75-1细胞中表达。更重要的是，我们发现了KGF对抗癌药物诱导MCF7细胞凋亡的抑制作用。总之，我们的结果表明，ER a可能参与了KGF的表达，并且KGF在人类乳腺癌中可能起到抗凋亡作用，而不是促有丝分裂作用。
Although estrogen is known to play a crucial role in the pathogenesis of breast cancer, the molecular mechanisms underlying the action of estrogen remain elusive. In the present study, we focused on keratinocyte growth factor (KGF) and its receptor (KGFR) in the pathogenesis of breast cancer, as a growth factor mediating estrogen action, since significant roles of KGF were demonstrated in various steroid hormone-dependent tissues. First, using paraffin-embedded specimens from 42 breast cancer patients, we examined expression patterns of KGF and KGFR by both immunohistochemistry using newly generated antibodies and nonradioactive in situ hybridization with T - T dimerized synthetic oligonucleotide probes. We next compared the results with the expression of estrogen receptor (ER) alpha and beta, proliferative activity and apoptotic frequency ( TUNEL staining). Also, the similar approaches were taken to analyze the expression and role of KGF in ER-positive (MCF7, ZR-75-1) and ER-negative (SK-BR-3, MDA-MB-231) human breast cancer cell lines in vitro. In the surgical specimens, KGF was expressed in cancer cells as well as stromal cells in 19/42 cases (45%), while KGFR was found in cancer cells in 24/42 cases (57%). The distribution of protein and mRNA in the analysis of both KGF and KGFR expression generally coincided. Moreover, KGF expression was closely associated with the expression of ER a, and the coexpression of KGF and KGFR significantly correlated with lower TUNEL index, but not with proliferative activity. In accordance with the in vivo findings, KGF expression was detected only in ER alpha-positive MCF7 and ZR-75-1 cells in vitro. And more importantly, we found the inhibitory effect of KGF upon the induction of apoptosis by anticancer drugs in MCF7 cells. Collectively, our results indicate that ER a may be involved in KGF expression, and that KGF may play antiapoptotic roles, rather than mitogenic, in human breast cancer.