Pescatori Sara, Berardinelli Francesco, Albanesi Jacopo, Ascenzi Paolo, Marino Maria, Antoccia Antonio, di Masi Alessandra, Acconcia Filippo
Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146 Rome, Italy.
Neurodevelopment, Neurogenetics and Molecular Neurobiology Unit, IRCCS Santa Lucia Foundation, 00143 Rome, Italy.
Cancers (Basel). 2021 Mar 30;13(7):1583. doi: 10.3390/cancers13071583.
17β-estradiol (E2) regulates human physiology both in females and in males. At the same time, E2 acts as a genotoxic substance as it could induce DNA damages, causing the initiation of cellular transformation. Indeed, increased E2 plasma levels are a risk factor for the development of several types of cancers including breast cancer. This paradoxical identity of E2 undermines the foundations of the physiological definition of "hormone" as E2 works both as a homeostatic regulator of body functions and as a genotoxic compound. Here, (i) the molecular circuitries underlying this double face of E2 are reviewed, and (ii) a possible framework to reconcile the intrinsic discrepancies of the E2 function is reported. Indeed, E2 is a regulator of the DNA damage response, which this hormone exploits to calibrate its genotoxicity with its physiological effects. Accordingly, the genes required to maintain genome integrity belong to the E2-controlled cellular signaling network and are essential for the appearance of the E2-induced cellular effects. This concept requires an "upgrade" to the vision of E2 as a "genotoxic hormone", which balances physiological and detrimental pathways to guarantee human body homeostasis. Deregulation of this equilibrium between cellular pathways would determine the E2 pathological effects.
17β-雌二醇（E2）在女性和男性体内均调节人体生理机能。与此同时，E2作为一种基因毒性物质，能够诱导DNA损伤，引发细胞转化。事实上，血浆中E2水平升高是包括乳腺癌在内的多种癌症发生发展的一个风险因素。E2这种矛盾的特性破坏了“激素”生理定义的基础，因为E2既作为身体功能的稳态调节因子，又作为基因毒性化合物发挥作用。在此，（i）对E2这一双重特性背后的分子机制进行综述，（ii）报告一个可能协调E2功能内在差异的框架。的确，E2是DNA损伤反应的调节因子，该激素利用这一反应来校准其基因毒性及其生理效应。因此，维持基因组完整性所需的基因属于E2控制的细胞信号网络，并且对于E2诱导的细胞效应的出现至关重要。这一概念需要将对E2的认识“升级”为一种“基因毒性激素”，其平衡生理和有害途径以确保人体稳态。细胞途径之间这种平衡的失调将决定E2的病理效应。
