Ganguly Shinjini, Naik Divya, Muskara Andrew, Mian Omar Y
Cleveland Clinic Lerner Research Institute, Cleveland, OH.
Cleveland Clinic Taussig Cancer Center, Cleveland, OH.
Endocrinology. 2021 Jan 1;162(1). doi: 10.1210/endocr/bqaa177.
Endocrine-driven malignancies, including breast and prostate cancer, are among the most common human cancers. The relationship between sex steroid hormones (eg, androgen, estrogen, and progesterone), their cognate receptors, and genomic stability lie at the center of endocrine-driven cancer development, progression, and therapeutic resistance. A variety of direct and indirect mechanisms have been described that link steroid hormone signaling to the loss of genomic integrity that drives early carcinogenesis. These effects are often enriched within endocrine receptor cistromes, accounting for the high proportion of mutations and rearrangements in the region of hormone response elements. In other cases, the effects are generalized and rely on a complex array of genetic, epigenetic, and metabolic interactions. Both androgen and estrogen receptors directly modulate the DNA damage response by trans-activating DNA damage response genes and redirecting the cellular repair machinery in the wake of genotoxic stress. Here we review the key mechanistic underpinnings of the relationship between sex steroid hormone receptors and genomic stability. In addition, we summarize emerging research in this area and discuss important implications for cancer prevention and treatment.
包括乳腺癌和前列腺癌在内的内分泌驱动型恶性肿瘤是人类最常见的癌症之一。性甾体激素（如雄激素、雌激素和孕激素）、它们的同源受体与基因组稳定性之间的关系是内分泌驱动型癌症发生、发展及治疗耐药性的核心所在。已经描述了多种直接和间接机制，这些机制将甾体激素信号传导与驱动早期致癌作用的基因组完整性丧失联系起来。这些效应在内分泌受体顺反组中往往更为富集，这解释了激素反应元件区域中高比例的突变和重排现象。在其他情况下，这些效应具有普遍性，并且依赖于一系列复杂的遗传、表观遗传和代谢相互作用。雄激素受体和雌激素受体都通过反式激活DNA损伤反应基因以及在基因毒性应激后重新引导细胞修复机制，直接调节DNA损伤反应。在此，我们综述性甾体激素受体与基因组稳定性之间关系的关键机制基础。此外，我们总结了该领域的新兴研究，并讨论了其对癌症预防和治疗的重要意义。
