Nicholson Robert I, Gee Julia M W, Knowlden Janice, McClelland Richard, Madden Tracie-Ann, Barrow Denise, Hutcheson Iain
Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, Cardiff, UK.
Breast Cancer Res Treat. 2003;80 Suppl 1:S29-34; discussion S35. doi: 10.1023/a:1025467500433.
Many estrogen receptor-positive breast cancer patients initially respond to treatment with antihormonal agents such as tamoxifen, but remissions are often followed by acquisition of resistance and ultimately disease relapse. The development of a rationale for the effective treatment of tamoxifen-resistant breast cancer requires an understanding of the complex signal transduction mechanisms that contribute towards loss of antiestrogen response. Interactions between estrogen and growth factor signaling pathways have been identified in estrogen-responsive cells that are thought to reinforce their individual cellular effects on growth and gene responses. Increasing evidence indicates that abnormalities occurring in growth factor signaling pathways, notably the epidermal growth factor receptor (EGFR) signaling pathway, could dramatically influence steroid hormone action and may be critical to antihormonal-resistant breast cancer cell growth. Thus, inhibitory agents targeting growth factor receptors, or their intracellular pathway components, may prove clinically beneficial in antihormone refractory disease. One example, gefitinib ('Iressa', ZD1839), an EGFR-tyrosine kinase inhibitor, is an interesting therapeutic option that may provide benefit in the treatment of antihormonal-resistant breast cancer. Rapid progress with pharmacological and molecular therapeutic agents is now being made. Therapies that target growth factor signaling pathways may prevent development of resistance.
许多雌激素受体阳性的乳腺癌患者最初对他莫昔芬等抗激素药物治疗有反应，但缓解后常出现耐药并最终导致疾病复发。要为他莫昔芬耐药性乳腺癌的有效治疗找到合理依据，就需要了解导致抗雌激素反应丧失的复杂信号转导机制。在雌激素反应性细胞中已发现雌激素和生长因子信号通路之间的相互作用，这些相互作用被认为会增强它们各自对细胞生长和基因反应的影响。越来越多的证据表明，生长因子信号通路，尤其是表皮生长因子受体（EGFR）信号通路中出现的异常，可能会显著影响类固醇激素的作用，并且可能对抗激素耐药性乳腺癌细胞的生长至关重要。因此，靶向生长因子受体或其细胞内通路成分的抑制剂可能在抗激素难治性疾病中具有临床益处。一个例子是吉非替尼（“易瑞沙”，ZD1839），一种EGFR酪氨酸激酶抑制剂，是一种有趣的治疗选择，可能在抗激素耐药性乳腺癌的治疗中发挥作用。目前在药理和分子治疗药物方面正在取得快速进展。靶向生长因子信号通路的疗法可能会预防耐药性的产生。
