Okubo S, Kurebayashi J, Otsuki T, Yamamoto Y, Tanaka K, Sonoo H
Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan.
Br J Cancer. 2004 Jan 12;90(1):236-44. doi: 10.1038/sj.bjc.6601504.
A high expression level of epidermal growth factor receptor (EGFR)/HER1 has been suggested to lead to a shorter survival time and resistance to endocrine therapy in patients with breast cancer. To test the hypothesis that inhibition of the EGFR signalling pathway affects the antitumour effect of endocrine therapy, an EGFR tyrosine kinase inhibitor (EGFR-TKI), gefitinib, and an oestrogen receptor (ER) antagonist, fulvestrant, were administered to human breast cancer cells. A total of five human breast cancer cell lines were used. The effects of single or combined treatments with gefitinib and/or fulvestrant on cell growth, cell cycle progression and apoptosis were analysed. Changes in the expression levels of cyclin-dependent kinase inhibitors, p21 and p27, an antiapoptotic factor, Bcl-2, and a proapoptotic factor, Bax, were also investigated. All cell lines tested were sensitive to gefitinib (50% growth inhibitory concentration, 10-28.5 microM). Breast cancer cell lines with a high expression level of HER1 or HER2 were more sensitive to gefitinib than the others. Gefitinib induced a significant G1-S blockade in ER-positive KPL-3C cells. Gefitinib induced significant apoptosis in HER1-overexpressing MDA-MB-231 cells. Gefitinib additively increased the antitumour effect of fulvestrant in all three ER-positive cell lines in a medium supplemented with 17beta-oestradiol. The combined treatment promoted cell cycle retardation in KPL-3C cells, which is associated with an upregulation of p21 by fulvestrant and gefitinib, respectively. Apoptosis was associated with downregulation of Bcl-2 by gefitinib in MDA-MB-231 cells. These results suggest an additive interaction between the EGFR-TKI gefitinib and the antioestrogen fulvestrant in ER-positive breast cancer cells.
表皮生长因子受体（EGFR）/HER1的高表达水平被认为会导致乳腺癌患者的生存时间缩短以及对内分泌治疗产生耐药性。为了验证抑制EGFR信号通路会影响内分泌治疗抗肿瘤效果这一假说，将一种EGFR酪氨酸激酶抑制剂（EGFR-TKI）吉非替尼和一种雌激素受体（ER）拮抗剂氟维司群应用于人类乳腺癌细胞。总共使用了5种人类乳腺癌细胞系。分析了吉非替尼和/或氟维司群单药或联合治疗对细胞生长、细胞周期进程和细胞凋亡的影响。还研究了细胞周期蛋白依赖性激酶抑制剂p21和p27、抗凋亡因子Bcl-2以及促凋亡因子Bax表达水平的变化。所有测试的细胞系对吉非替尼均敏感（50%生长抑制浓度，10 - 28.5微摩尔）。HER1或HER2高表达的乳腺癌细胞系比其他细胞系对吉非替尼更敏感。吉非替尼在ER阳性的KPL-3C细胞中诱导了显著的G1-S期阻滞。吉非替尼在HER1过表达的MDA-MB-231细胞中诱导了显著的细胞凋亡。在补充有17β-雌二醇的培养基中，吉非替尼在所有三种ER阳性细胞系中均增强了氟维司群的抗肿瘤效果。联合治疗促进了KPL-3C细胞的细胞周期阻滞，这分别与氟维司群和吉非替尼上调p21有关。在MDA-MB-231细胞中，细胞凋亡与吉非替尼下调Bcl-2有关。这些结果表明，在ER阳性乳腺癌细胞中，EGFR-TKI吉非替尼和抗雌激素氟维司群之间存在相加作用。
