Maximov Philipp Y, Lewis-Wambi Joan S, Jordan V Craig
Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Curr Signal Transduct Ther. 2009 May 1;4(2):88-102. doi: 10.2174/157436209788167484.
High dose oestrogen therapy was used as a treatment for postmenopausal patients with breast cancer from the 1950s until the introduction of the safer antioestrogen, tamoxifen in the 1970s. The anti-tumour mechanism of high dose oestrogen therapy remained unknown. There was no enthusiasm to study these signal transduction pathways as oestrogen therapy has almost completely been eliminated from the treatment paradigm. Current use of tamoxifen and the aromatase inhibitors seek to create oestrogen deprivation that prevents the growth of oestrogen stimulated oestrogen receptor (ER) positive breast cancer cells. However, acquired resistance to antihormonal therapy does occur, but it is through investigation of laboratory models that a vulnerability of the cancer cell has been discovered and is being investigated to provide new opportunities in therapy with the potential for discovering new cancer-specific apoptotic drugs. Laboratory models of resistance to raloxifene and tamoxifen, the selective oestrogen receptor modulators (SERMs) and aromatase inhibitors demonstrate an evolution of drug resistance so that after many years of oestrogen deprivation, the ER positive cancer cell reconfigures the survival signal transduction pathways so oestrogen now becomes an apoptotic trigger rather than a survival signal. Current efforts are evaluating the mechanisms of oestrogen-induced apoptosis and how this new biology of oestrogen action can be amplified and enhanced, thereby increasing the value of this therapeutic opportunity for the treatment of breast cancer. Several synergistic approaches to therapeutic enhancement are being advanced which involve drug combinations to impair survival signaling with the use of specific agents and to impair bcl-2 that protects the cancer cell from apoptosis. We highlight the historical understanding of oestrogen's role in cell survival and death and specifically illustrate the progress that has been made in the last five years to understand the mechanisms of oestrogen-induced apoptosis. There are opportunities to harness knowledge from this new signal transduction pathway to discover the precise mechanism of this oestrogen-induced apoptotic trigger. Indeed, the new biology of oestrogen action also has significance for understanding the physiology of bone remodeling. Thus, the pathway has a broad appeal in both physiology and cancer research.
从20世纪50年代到70年代更安全的抗雌激素药物他莫昔芬问世之前，高剂量雌激素疗法一直被用于治疗绝经后乳腺癌患者。高剂量雌激素疗法的抗肿瘤机制尚不清楚。由于雌激素疗法几乎已完全从治疗模式中被淘汰，因此人们对研究这些信号转导途径缺乏热情。目前使用的他莫昔芬和芳香化酶抑制剂旨在造成雌激素剥夺，以阻止雌激素刺激的雌激素受体（ER）阳性乳腺癌细胞的生长。然而，确实会出现对抗激素疗法的获得性耐药，但正是通过对实验室模型的研究，发现了癌细胞的一个弱点，并正在对其进行研究，以期为治疗提供新的机会，有可能发现新的癌症特异性凋亡药物。对雷洛昔芬和他莫昔芬（选择性雌激素受体调节剂，SERM）以及芳香化酶抑制剂耐药的实验室模型显示出耐药性的演变，因此在多年的雌激素剥夺后，ER阳性癌细胞会重新配置生存信号转导途径，使得雌激素现在成为一种凋亡触发因素而非生存信号。目前正在努力评估雌激素诱导凋亡的机制，以及如何放大和增强这种雌激素作用的新生物学特性，从而增加这种治疗机会对乳腺癌治疗的价值。正在推进几种协同增强治疗的方法，包括使用特定药物联合来破坏生存信号，并破坏保护癌细胞免于凋亡的bcl-2。我们强调了对雌激素在细胞存活和死亡中作用的历史认识，并特别阐述了在过去五年中在理解雌激素诱导凋亡机制方面所取得的进展。有机会利用来自这条新信号转导途径的知识来发现这种雌激素诱导凋亡触发因素的确切机制。事实上，雌激素作用的新生物学特性对于理解骨重塑的生理学也具有重要意义。因此，这条途径在生理学和癌症研究中都具有广泛的吸引力。
