Kurebayashi Junichi, Okubo Sumiko, Yamamoto Yutaka, Sonoo Hiroshi
Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan.
Breast Cancer. 2004;11(1):38-41. doi: 10.1007/BF02968000.
Epidermal growth factor receptor (EGFR)/HER1 is expressed at high levels in at least 20% of breast cancers. This high expression correlates with a poor prognosis in patients with breast cancer. Experimental and clinical findings suggest that aberrant activation of tyrosine receptor kinases, such as HER1 pathway, play a causal role in the development of antiestrogen resistance in breast cancer. Recent preclinical and clinical evidence shows that inhibition of growth factor signaling pathways suppresses the growth of malignant cells without serious toxicities. To test the hypothesis that inhibition of the HER1 signaling pathway enhances the antitumor effect of endocrine therapy, a promising signal transduction inhibitor (STI) of HER1 tyrosine kinase, gefitinib, and an estrogen receptor (ER) antagonist, fulvestrant, were administered to human breast cancer cells. Our experimental results have revealed that gefitinib additively enhances the antitumor effect of fulvestrant in estrogen receptor (ER)-positive breast cancer cells under estrogen-supplemented conditions. An additive increase in the protein expression level of a cyclin-dependent kinase inhibitor, p21 may play a key role of this additive cytostatic effect. The rationale and future perspectives of the combined use of STIs with endocrine therapy in breast cancer are discussed.
表皮生长因子受体（EGFR）/HER1在至少20%的乳腺癌中高表达。这种高表达与乳腺癌患者的不良预后相关。实验和临床研究结果表明，酪氨酸受体激酶的异常激活，如HER1信号通路，在乳腺癌抗雌激素耐药的发生中起因果作用。最近的临床前和临床证据表明，抑制生长因子信号通路可抑制恶性细胞的生长且无严重毒性。为了验证抑制HER1信号通路可增强内分泌治疗抗肿瘤效果这一假说，将一种有前景的HER1酪氨酸激酶信号转导抑制剂（STI）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。我们的实验结果显示，在补充雌激素的条件下，吉非替尼可增强氟维司群对雌激素受体（ER）阳性乳腺癌细胞的抗肿瘤作用。细胞周期蛋白依赖性激酶抑制剂p21蛋白表达水平的相加性增加可能在这种相加性细胞生长抑制作用中起关键作用。本文讨论了STIs与内分泌治疗联合用于乳腺癌的理论基础和未来前景。
