Fan Ping, Craig Jordan V
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC 20057, United States.
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC 20057, United States.
Steroids. 2014 Nov;90:44-52. doi: 10.1016/j.steroids.2014.06.002. Epub 2014 Jun 12.
Tamoxifen, a pioneering selective estrogen receptor modulator (SERM), has long been a therapeutic choice for all stages of estrogen receptor (ER)-positive breast cancer. The clinical application of long-term adjuvant antihormone therapy for the breast cancer has significantly improved breast cancer survival. However, acquired resistance to SERM remains a significant challenge in breast cancer treatment. The evolution of acquired resistance to SERMs treatment was primarily discovered using MCF-7 tumors transplanted in athymic mice to mimic years of adjuvant treatment in patients. Acquired resistance to tamoxifen is unique because the growth of resistant tumors is dependent on SERMs. It appears that acquired resistance to SERM is initially able to utilize either E2 or a SERM as the growth stimulus in the SERM-resistant breast tumors. Mechanistic studies reveal that SERMs continuously suppress nuclear ER-target genes even during resistance, whereas they function as agonists to activate multiple membrane-associated molecules to promote cell growth. Laboratory observations in vivo further show that three phases of acquired SERM-resistance exists, depending on the length of SERMs exposure. Tumors with Phase I resistance are stimulated by both SERMs and estrogen. Tumors with Phase II resistance are stimulated by SERMs, but are inhibited by estrogen due to apoptosis. The laboratory models suggest a new treatment strategy, in which limited-duration, low-dose estrogen can be used to purge Phase II-resistant breast cancer cells. This discovery provides an invaluable insight into the evolution of drug resistance to SERMs, and this knowledge is now being used to justify clinical trials of estrogen therapy following long-term antihormone therapy. All of these results suggest that cell populations that have acquired resistance are in constant evolution depending upon selection pressure. The limited availability of growth stimuli in any new environment enhances population plasticity in the trial and error search for survival.
他莫昔芬是一种开创性的选择性雌激素受体调节剂（SERM），长期以来一直是雌激素受体（ER）阳性乳腺癌各阶段的治疗选择。乳腺癌长期辅助抗激素治疗的临床应用显著提高了乳腺癌患者的生存率。然而，对SERM产生获得性耐药仍然是乳腺癌治疗中的一个重大挑战。对SERM治疗获得性耐药的演变主要是通过将MCF-7肿瘤移植到无胸腺小鼠体内来模拟患者多年的辅助治疗而发现的。对他莫昔芬的获得性耐药具有独特性，因为耐药肿瘤的生长依赖于SERM。似乎对SERM的获得性耐药最初能够利用E2或SERM作为SERM耐药性乳腺癌肿瘤中的生长刺激因素。机制研究表明，即使在耐药期间，SERM也会持续抑制核ER靶基因，而它们作为激动剂激活多种膜相关分子以促进细胞生长。体内实验室观察进一步表明，根据SERM暴露的时长，存在三个阶段的获得性SERM耐药。具有I期耐药的肿瘤受到SERM和雌激素的刺激。具有II期耐药的肿瘤受到SERM的刺激，但由于凋亡而受到雌激素的抑制。实验室模型提出了一种新的治疗策略，即可以使用有限时长、低剂量的雌激素来清除II期耐药的乳腺癌细胞。这一发现为对SERM耐药性的演变提供了宝贵的见解，并且这一知识现在正被用于证明长期抗激素治疗后雌激素治疗临床试验的合理性。所有这些结果表明，获得耐药性的细胞群体根据选择压力在不断演变。在任何新环境中生长刺激因素的有限可用性增强了群体可塑性，使其在试错中寻求生存。
