New insights on the role of hormonal therapy in ovarian cancer.
New insights on the role of hormonal therapy in ovarian cancer.
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关于荷尔蒙治疗在卵巢癌中作用的新见解。
DOI：
10.1016/j.steroids.2013.01.008
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发表时间：
2013-06
期刊：
影响因子：
2.7
通讯作者：
Slingerland J
中科院分区：
文献类型：
--
作者：
Simpkins F;Garcia-Soto A;Slingerland J
卵巢癌（Ovarian cancer，OVCA）是妇科最致命的恶性肿瘤。它通常在晚期被诊断出来，尽管有治疗，70%的患者在2年内复发，患有不治之症。迫切需要具有临床益处和最小毒性的方案。在这种情况下，更有效的激素疗法将是有吸引力的。雌激素（E2）与OVCA的病因有关。雌激素促进增殖，抗雌激素抑制体外和体内卵巢癌生长。尽管雌激素受体（ER）的表达在67%的卵巢癌，小抗雌激素治疗试验一直令人失望，激素治疗的好处还没有系统地研究了大型精心设计的试验。OVCAs通常表现出从头抗雌激素抗性，并且最初应答的那些总是发展抗性。雌激素通过转录激活和配体ER和促有丝分裂通路之间的串扰刺激卵巢癌进展，这两者都驱动细胞周期进展。雌激素剥夺和雌激素受体（ER）阻断通过增加细胞周期抑制因子p27而引起敏感OVCA的细胞周期阻滞。这篇综述总结和讨论了支持雌激素在卵巢癌发生中作用的科学和流行病学证据，概述了雌激素受体阻断剂和芳香化酶抑制剂在OVCA中的临床试验，并回顾了抗雌激素抵抗的潜在原因。抗雌激素抵抗最近被证明是逆转的双重ER和Src信号传导阻滞。阻断ER和组成性激活激酶通路之间的串扰可能会改善OVCA中的抗雌激素治疗效果，正如在其他癌症中所证明的那样。新的战略，以提高抗雌激素的好处相结合的靶向治疗。
Ovarian cancer (OVCA) is the most lethal gynecological malignancy. It is often diagnosed in advanced stages and despite therapy, 70% relapse within 2 years with incurable disease. Regimens with clinical benefit and minimal toxicity are urgently needed. More effective hormonal therapies would be appealing in this setting. Estrogens (E2) are implicated in the etiology of OVCA. Estrogens drive proliferation and anti-estrogens inhibit ovarian cancer growth in vitro and in vivo. Despite estrogen receptor (ER) expression in 67% of OVCAs, small anti-estrogen therapy trials have been disappointing and the benefit of hormonal therapy has not been systematically studied in large well-designed trials. OVCAs often manifest de novo anti-estrogen resistance and those that initially respond invariably develop resistance. Estrogens stimulate ovarian cancer progression by transcriptional activation and cross talk between liganded ER and mitogenic pathways, both of which drive cell cycle progression. Estrogen deprivation and estrogen receptor (ER) blockade cause cell cycle arrest in susceptible OVCAs by increasing the cell cycle inhibitor, p27. This review summarizes and discusses scientific and epidemiological evidence supporting estrogen’s role in ovarian carcinogenesis, provides an overview of clinical trials of ER blockade and aromatase inhibitors in OVCA and reviews potential causes of antiestrogen resistance. Anti-estrogen resistance was recently shown to be reversed by dual ER and Src signaling blockade. Blocking cross-talk between ER and constitutively activated kinase pathways may improve anti-estrogen therapeutic efficacy in OVCA, as has been demonstrated in other cancers. Novel strategies to improve benefit from anti-estrogens by combining them with targeted therapies are reviewed.