Anbalagan Muralidharan, Rowan Brian G
Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA.
Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA.
Mol Cell Endocrinol. 2015 Dec 15;418 Pt 3:264-72. doi: 10.1016/j.mce.2015.01.016. Epub 2015 Jan 15.
Estrogen receptor α (ERα) is a member of the nuclear receptor superfamily of transcription factors that regulates cell proliferation, differentiation and homeostasis in various tissues. Sustained exposure to estrogen/estradiol (E2) increases the risk of breast, endometrial and ovarian cancers. ERα function is also regulated by phosphorylation through various kinase signaling pathways that will impact various ERα functions including chromatin interaction, coregulator recruitment and gene expression, as well impact breast tumor growth/morphology and breast cancer patient response to endocrine therapy. However, many of the previously characterized ERα phosphorylation sites do not fully explain the impact of receptor phosphorylation on ERα function. This review discusses work from our laboratory toward understanding a role of ERα site-specific phosphorylation in ERα function and breast cancer. The key findings discussed in this review are: (1) the effect of site specific ERα phosphorylation on temporal recruitment of ERα and unique coactivator complexes to specific genes; (2) the impact of stable disruption of ERα S118 and S167 phosphorylation in breast cancer cells on eliciting unique gene expression profiles that culminate in significant effects on breast cancer growth/morphology/migration/invasion; (3) the Src kinase signaling pathway that impacts ERα phosphorylation to alter ERα function; and (4) circadian disruption by light exposure at night leading to elevated ERK1/2 and Src kinase and phosphorylation of ERα, concomitant with tamoxifen resistance in breast tumor models. Results from these studies demonstrate that even changes to single ERα phosphorylation sites can have a profound impact on ERα function in breast cancer. Future work will extend beyond single site phosphorylation analysis toward identification of specific patterns/profiles of ERα phosphorylation under different physiological/pharmacological conditions to understand how common phosphorylation profiles in breast cancer program specific physiological endpoints such as growth, apoptosis, migration/invasion, and endocrine therapy response.
雌激素受体α（ERα）是转录因子核受体超家族的成员，可调节多种组织中的细胞增殖、分化和内环境稳定。持续暴露于雌激素/雌二醇（E2）会增加患乳腺癌、子宫内膜癌和卵巢癌的风险。ERα的功能也通过各种激酶信号通路的磷酸化来调节，这将影响包括染色质相互作用、共调节因子募集和基因表达在内的各种ERα功能，以及乳腺癌的生长/形态和乳腺癌患者对内分泌治疗的反应。然而，许多先前已鉴定的ERα磷酸化位点并不能完全解释受体磷酸化对ERα功能的影响。本综述讨论了我们实验室为了解ERα位点特异性磷酸化在ERα功能和乳腺癌中的作用所做的工作。本综述中讨论的主要发现包括：（1）ERα位点特异性磷酸化对ERα和独特共激活因子复合物向特定基因的时间募集的影响；（2）乳腺癌细胞中ERα S118和S167磷酸化的稳定破坏对引发独特基因表达谱的影响，这些基因表达谱最终对乳腺癌的生长/形态/迁移/侵袭产生显著影响；（3）影响ERα磷酸化以改变ERα功能的Src激酶信号通路；（4）夜间光照导致昼夜节律紊乱，从而导致ERK1/2和Src激酶升高以及ERα磷酸化，同时在乳腺肿瘤模型中出现他莫昔芬耐药。这些研究结果表明，即使是单个ERα磷酸化位点的变化也可能对乳腺癌中ERα的功能产生深远影响。未来的工作将超越单一位点磷酸化分析，朝着识别不同生理/药理条件下ERα磷酸化的特定模式/谱展开，以了解乳腺癌中常见的磷酸化谱如何调控特定的生理终点，如生长、凋亡、迁移/侵袭和内分泌治疗反应。
