Animal Facility, Istituto Nazionale Tumori - "Fondazione G. Pascale" - IRCCS, 80131 Naples, Italy.
Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081 Salerno, Italy.
Front Biosci (Landmark Ed). 2022 Jul 14;27(7):223. doi: 10.31083/j.fbl2707223.
Breast cancer is the most common malignancy among women worldwide. Several studies indicate that, in addition to established risk factors for breast cancer, other factors such as cortisol release related to psychological stress and drug treatment with high levels of glucocorticoids may also contribute significantly to the initiation of breast cancer. There are several possible mechanisms by which glucocorticoids might promote neoplastic transformation of breast tissue. Among these, the least known and studied is the inhibition of the nuclear erythroid factor 2-related (Nrf2)-antioxidant/electrophile response element (ARE/EpRE) pathway by high levels of glucocorticoids. Specifically, Nrf2 is a potent transcriptional activator that plays a central role in the basal and inducible expression of many cytoprotective genes that effectively protect mammalian cells from various forms of stress and reduce the propensity of tissues and organisms to develop disease or malignancy including breast cancer. Consequently, a loss of Nrf2 in response to high levels of gluco-corticoids may lead to a decrease in cellular defense against oxidative stress, which plays an important role in the initiation of human mammary carcinogenesis. In the present review, we provide a comprehensive overview of the current state of knowledge of the cellular mechanisms by which both glucocorticoid pharmacotherapy and endogenous GCs (cortisol in humans and corticosterone in rodents) may contribute to breast cancer development through inhibition of the Nrf2-ARE/EpRE pathway and the protective role of melatonin against glucocorticoid-induced apoptosis in the immune system.
乳腺癌是全球女性中最常见的恶性肿瘤。有几项研究表明，除了乳腺癌的既定风险因素外，其他因素，如与心理压力相关的皮质醇释放和高剂量糖皮质激素药物治疗，也可能对乳腺癌的发生有重要贡献。糖皮质激素可能促进乳腺组织发生肿瘤转化的机制有几种。其中，研究最少且知之甚少的是高水平糖皮质激素对核红细胞因子 2 相关（Nrf2）-抗氧化剂/亲电体反应元件（ARE/EpRE）途径的抑制作用。具体来说，Nrf2 是一种有效的转录激活因子，在许多细胞保护基因的基础和诱导表达中发挥核心作用，这些基因有效地保护哺乳动物细胞免受各种形式的应激，并降低组织和生物体发生疾病或恶性肿瘤（包括乳腺癌）的倾向。因此，对高水平糖皮质激素的 Nrf2 反应丧失可能导致细胞对氧化应激的防御能力下降，氧化应激在人类乳腺致癌发生中起着重要作用。在本综述中，我们全面概述了目前对细胞机制的认识，即糖皮质激素药物治疗和内源性 GCs（人类的皮质醇和啮齿动物的皮质酮）如何通过抑制 Nrf2-ARE/EpRE 途径促进乳腺癌的发展，以及褪黑素对糖皮质激素诱导的免疫系统细胞凋亡的保护作用。
