Huang Jing, Li Xiaodong, Hilf Russell, Bambara Robert A, Muyan Mesut
Department of Biochemistry and Biophysics, University of Rochester Medical Center, 601 Elmwood Avenue, Box 712, NY 14642, USA.
Curr Drug Targets Immune Endocr Metabol Disord. 2005 Dec;5(4):379-96. doi: 10.2174/156800805774912944.
The development of breast cancer is the consequence of uncontrolled growth and division of breast-ductal epithelial cells. While many factors contribute to its etiology, estrogen hormones within the context of many interrelated growth signaling pathways play critical roles for the initiation and development of breast cancer. The effects of estrogens are primarily mediated by the estrogen receptors (ERs) alpha and beta. ER mediates a complex array of genomic and non-genomic events that orchestrate cellular metabolism, mitogenesis, morphogenesis, motogenesis, and apoptosis. The current modalities for the treatment of breast cancer have centered on the development of agents with diverse pharmacology to reduce/ablate the circulating estrogens or to alter/prevent ER function. Approaches to perturb the estrogen environment are successful usually in the remission of established tumors. However, many breast tumors are not responsive or eventually develop resistance to endocrine therapies. Despite considerable effort, the mechanism for the non-responsiveness and acquisition of resistance remains unclear. The establishment of hormone responsiveness is one of the current approaches for the development of an effective therapeutic modality for de novo resistant breast tumors. Re-establishment of loss of ER synthesis/function, on the other hand, constitutes a primary therapeutic goal for acquired resistance neoplasms. We have recently engineered transregulatory proteins that specifically targeted and robustly regulated estrogen responsive genes independent of ligand, ER-subtype and cell-context. The targeted regulation of estrogen responsive gene networks by these designer transregulators could provide a basis for the development of novel approaches for experimental biology and medicine.
乳腺癌的发生是乳腺导管上皮细胞不受控制地生长和分裂的结果。虽然许多因素导致其病因，但在许多相互关联的生长信号通路背景下的雌激素在乳腺癌的发生和发展中起着关键作用。雌激素的作用主要由雌激素受体（ERs）α和β介导。ER介导一系列复杂的基因组和非基因组事件，这些事件协调细胞代谢、有丝分裂、形态发生、运动发生和细胞凋亡。目前治疗乳腺癌的方式主要集中在开发具有不同药理学特性的药物，以减少/消除循环雌激素或改变/预防ER功能。干扰雌激素环境的方法通常在已建立的肿瘤缓解方面取得成功。然而，许多乳腺肿瘤对内分泌治疗无反应或最终产生耐药性。尽管付出了巨大努力，但无反应和获得耐药性的机制仍不清楚。建立激素反应性是目前开发针对原发性耐药乳腺肿瘤的有效治疗方式的方法之一。另一方面，重新建立ER合成/功能的丧失是获得性耐药肿瘤的主要治疗目标。我们最近设计了一些反式调节蛋白，它们能够独立于配体、ER亚型和细胞环境，特异性地靶向并强力调节雌激素反应基因。这些设计的反式调节因子对雌激素反应基因网络的靶向调节可为实验生物学和医学新方法的开发提供基础。
