表皮生长因子受体抑制剂对雌激素受体阴性乳腺肿瘤发生发展的影响。

Effect of epidermal growth factor receptor inhibitor on development of estrogen receptor-negative mammary tumors.

作者信息

Lu Chunhua, Speers Corey, Zhang Yun, Xu Xiaochun, Hill Jamal, Steinbis Emily, Celestino Joseph, Shen Qiang, Kim Heetae, Hilsenbeck Susan, Mohsin Syed K, Wakeling Alan, Osborne C Kent, Brown Powel H

机构信息

Department of Medicine, Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.

出版信息

J Natl Cancer Inst. 2003 Dec 17;95(24):1825-33. doi: 10.1093/jnci/djg117.

DOI:10.1093/jnci/djg117

PMID:14679152

Abstract

BACKGROUND

Although antiestrogens have been effective in preventing estrogen receptor (ER)-positive breast cancer, chemopreventive agents are still needed to prevent ER-negative breast cancer. Tyrosine kinase inhibitors are promising agents for the treatment and prevention of human cancers. ZD1839 (gefitinib or Iressa) is an orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that blocks signal transduction pathways in epithelial cells. We examined whether ZD1839 blocks signal transduction and prevents the development of ER-negative breast cancer.

METHODS

The ability of ZD1839 to block signal transduction in normal, immortalized, and malignant breast cells was assessed by western blotting with specific antibodies to detect phosphorylation of cytoplasmic signaling molecules. The effect of ZD1839 on growth of these breast cells was assessed with anchorage-dependent and anchorage-independent growth assays. Its effect on ER-negative mammary tumorigenesis was assessed in MMTV-erbB2 transgenic mice. All statistical tests were two-sided.

RESULTS

ZD1839 suppressed the phosphorylation of EGFR and mitogen-activated protein kinase in normal and malignant breast cells. ZD1839 treatment statistically significantly suppressed mammary tumorigenesis in MMTV-erbB2 transgenic mice; median time to tumor development was approximately 230 days in vehicle-treated mice and more than 310 days in mice treated with ZD1839 at 100 mg/kg (P<.001). ZD1839 reduced proliferation of normal breast cells by 20.3% (95% confidence interval [CI] = -13.7% to 44.2%) and of tumor cells by 42.0% (95% CI = 20.2% to 58.2%). ZD1839 also increased expression of the cell cycle regulator p27 in normal mammary tissue by 48.7% (95% CI = 27.0% to 74.2%) and in tumor tissue by 50.3% (95% CI = 35.8% to 66.7%).

CONCLUSION

This study appears to provide the preclinical rationale for the development of these EGFR tyrosine kinase inhibitors for the prevention of human breast cancer.

摘要

背景

尽管抗雌激素药物在预防雌激素受体（ER）阳性乳腺癌方面已取得成效，但仍需要化学预防药物来预防ER阴性乳腺癌。酪氨酸激酶抑制剂是治疗和预防人类癌症的有前景的药物。ZD1839（吉非替尼或易瑞沙）是一种口服活性表皮生长因子受体（EGFR）酪氨酸激酶抑制剂，可阻断上皮细胞中的信号转导途径。我们研究了ZD1839是否能阻断信号转导并预防ER阴性乳腺癌的发生。

方法

通过使用特异性抗体进行蛋白质印迹法检测细胞质信号分子的磷酸化，评估ZD1839在正常、永生化和恶性乳腺细胞中阻断信号转导的能力。通过贴壁依赖性和非贴壁依赖性生长试验评估ZD1839对这些乳腺细胞生长的影响。在MMTV-erbB2转基因小鼠中评估其对ER阴性乳腺肿瘤发生的影响。所有统计检验均为双侧检验。

结果

ZD1839可抑制正常和恶性乳腺细胞中EGFR和丝裂原活化蛋白激酶的磷酸化。ZD1839治疗在统计学上显著抑制了MMTV-erbB2转基因小鼠的乳腺肿瘤发生；在给予载体处理的小鼠中，肿瘤发生的中位时间约为230天，而在给予100 mg/kg ZD1839治疗的小鼠中，超过310天（P<0.001）。ZD1839使正常乳腺细胞的增殖减少20.3%（95%置信区间[CI]=-13.7%至44.2%），使肿瘤细胞的增殖减少42.0%（95%CI=20.2%至58.2%）。ZD1839还使正常乳腺组织中细胞周期调节因子p27的表达增加48.7%（95%CI=27.0%至74.2%），在肿瘤组织中增加50.3%（95%CI=35.8%至66.7%）。