Columbia University Vagelos College of Physicians and Surgeons, New York, New York 10032, USA.
The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
Endocrinology. 2021 Aug 1;162(8). doi: 10.1210/endocr/bqab088.
Breast cancer is a highly heterogeneous disease, encompassing many subtypes that have distinct origins, behaviors, and prognoses. Although traditionally seen as a genetic disease, breast cancer is now also known to involve epigenetic abnormalities. Epigenetic regulators, such as DNA methyltransferases and histone-modifying enzymes, play essential roles in gene regulation and cancer development. Dysregulation of epigenetic regulator activity has been causally linked with breast cancer pathogenesis. Hairless (HR) encodes a 130-kDa transcription factor that is essential for development and tissue homeostasis. Its role in transcription regulation is partly mediated by its interaction with multiple nuclear receptors, including thyroid hormone receptor, retinoic acid receptor-related orphan receptors, and vitamin D receptor. HR has been studied primarily in epidermal development and homeostasis. Hr-mutant mice are highly susceptible to ultraviolet- or carcinogen-induced skin tumors. Besides its putative tumor suppressor function in skin, loss of HR function has also been implicated in increased leukemia susceptibility and promotes the growth of melanoma and brain cancer cells. HR has also been demonstrated to function as a histone H3 lysine 9 demethylase. Recent genomics studies have identified HR mutations in a variety of human cancers, including breast cancer. The anticancer function and mechanism of action by HR in mammary tissue remains to be investigated. Here, we review the emerging role of HR, its histone demethylase activity and histone methylation in breast cancer development, and potential for epigenetic therapy.
乳腺癌是一种高度异质性的疾病，包括许多具有不同起源、行为和预后的亚型。尽管传统上被视为一种遗传性疾病，但现在也知道乳腺癌涉及表观遗传异常。表观遗传调节剂，如 DNA 甲基转移酶和组蛋白修饰酶，在基因调控和癌症发展中发挥着重要作用。表观遗传调节剂活性的失调与乳腺癌的发病机制有关。无毛（HR）编码一种 130kDa 的转录因子，对发育和组织稳态至关重要。其在转录调控中的作用部分是通过与多种核受体的相互作用介导的，包括甲状腺激素受体、视黄酸受体相关孤儿受体和维生素 D 受体。HR 主要在表皮发育和稳态中进行研究。Hr 突变小鼠对紫外线或致癌剂诱导的皮肤肿瘤高度敏感。除了在皮肤中作为潜在的肿瘤抑制因子的功能外，HR 功能的丧失也与白血病易感性增加有关，并促进黑色素瘤和脑癌细胞的生长。HR 还被证明是组蛋白 H3 赖氨酸 9 去甲基酶。最近的基因组学研究在多种人类癌症中发现了 HR 突变，包括乳腺癌。HR 在乳腺组织中的抗癌功能和作用机制仍有待研究。在这里，我们综述了 HR 的新兴作用、其在乳腺癌发展中的组蛋白去甲基酶活性和组蛋白甲基化，以及表观遗传治疗的潜力。
