Wright Tricia M, Wardell Suzanne E, Jasper Jeff S, Stice James P, Safi Rachid, Nelson Erik R, McDonnell Donald P
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.
Mol Cancer Res. 2014 Dec;12(12):1829-39. doi: 10.1158/1541-7786.MCR-14-0195. Epub 2014 Aug 6.
Tamoxifen, a selective estrogen receptor (ER) modulator (SERM), remains a frontline clinical therapy for patients with ERα-positive breast cancer. However, the relatively rapid development of resistance to this drug in the metastatic setting remains an impediment to a durable response. Although drug resistance likely arises by many different mechanisms, the consensus is that most of the implicated pathways facilitate the outgrowth of a subpopulation of cancer cells that can either recognize tamoxifen as an agonist or bypass the regulatory control of ERα. Notable in this regard is the observation here and in other studies that expression of anterior gradient homology 2 (AGR2), a known proto-oncogene and disulfide isomerase, was induced by both estrogen (17β-estradiol, E2) and 4-hydroxytamoxifen (4OHT) in breast cancer cells. The importance of AGR2 expression is highlighted here by the observation that (i) its knockdown inhibited the growth of both tamoxifen-sensitive and -resistant breast cancer cells and (ii) its increased expression enhanced the growth of ERα-positive tumors in vivo and increased the migratory capacity of breast cancer cells in vitro. Interestingly, as with most ERα target genes, the expression of AGR2 in all breast cancer cells examined requires the transcription factor FOXA1. However, in tamoxifen-resistant cells, the expression of AGR2 occurs in a constitutive manner, requiring FOXA1, but loses its dependence on ER. Taken together, these data define the importance of AGR2 in breast cancer cell growth and highlight a mechanism where changes in FOXA1 activity obviate the need for ER in the regulation of this gene.
These findings reveal the transcriptional interplay between FOXA1 and ERα in controlling AGR2 during the transition from therapy-sensitive to -resistant breast cancer and implicate AGR2 as a relevant therapeutic target.
他莫昔芬是一种选择性雌激素受体（ER）调节剂（SERM），仍然是雌激素受体α（ERα）阳性乳腺癌患者的一线临床治疗药物。然而，在转移性环境中对该药物相对迅速产生耐药性仍然是持久反应的一个障碍。尽管耐药性可能通过许多不同机制产生，但共识是，大多数涉及的途径促进了癌细胞亚群的生长，这些癌细胞要么将他莫昔芬识别为激动剂，要么绕过ERα的调节控制。在这方面值得注意的是，本研究以及其他研究观察到，在乳腺癌细胞中，已知的原癌基因和二硫键异构酶前梯度同源2（AGR2）的表达由雌激素（17β-雌二醇，E2）和4-羟基他莫昔芬（4OHT）诱导。AGR2表达的重要性在此通过以下观察结果得到强调：（i）其敲低抑制了他莫昔芬敏感和耐药乳腺癌细胞的生长；（ii）其表达增加增强了体内ERα阳性肿瘤的生长，并增加了体外乳腺癌细胞的迁移能力。有趣的是，与大多数ERα靶基因一样，AGR2在所有检测的乳腺癌细胞中的表达都需要转录因子FOXA1。然而，在他莫昔芬耐药细胞中，AGR2的表达以组成型方式发生，需要FOXA1，但失去了对ER的依赖性。综上所述，这些数据确定了AGR2在乳腺癌细胞生长中的重要性，并突出了一种机制，即FOXA1活性的变化消除了ER在该基因调控中的必要性。
这些发现揭示了在从治疗敏感型乳腺癌向耐药型乳腺癌转变过程中，FOXA1和ERα在控制AGR2方面的转录相互作用，并表明AGR2是一个相关的治疗靶点。
