Department of Clinical Biochemistry, Medical School, University of Athens, Attikon General University Hospital, 1 Rimini street, Chaidari, Athens 12462, Greece.
Med Hypotheses. 2012 Nov;79(5):617-21. doi: 10.1016/j.mehy.2012.07.036. Epub 2012 Aug 24.
Worldwide breast cancer (BC) constitutes a significant public health concern. Excess body weight is associated with postmenopausal BC (PBC) risk. Recent studies have shown that the constellation of obesity, insulin resistance and serum adipokine levels are associated with the risk and prognosis of PBC. Nicotinamide phosphoribosyl-transferase (Nampt), also known as visfatin and pre-B-cell-colony-enhancing factor, found in the visceral fat, represents a novel pleiotropic adipokine acting as a cytokine, a growth factor and an enzyme. It plays an important role in a variety of metabolic and stress responses as well as in the cellular energy metabolism, particularly NAD biosynthesis. Nampt exhibits proliferative, anti-apoptotic, pro-inflammatory and pro-angiogenic properties. Nampt's insulin-mimetic function remains a controversial issue. Circulating Nampt levels are increased in obese women. Also, Nampt levels are significantly elevated in women suffering from PBC than in healthy controls independently from known risk factors of BC, anthropometric and metabolic parameters as well as serum concentrations of well known adipokines. High expression of Nampt in BC tissues was reported to be associated with more malignant cancer behavior as well as adverse prognosis. Taking into account the mitogenicity of Nampt as well as its proliferative, anti-apoptotic and pro-angiogenic properties, a novel hypothesis is proposed whereas Nampt may be involved in the etiopathogenesis of PBC and may represent a missing link between overweight/obesity and PBC. Nampt could exert its effects on the normal and neoplastic mammary tissue by endocrine and paracrine mechanisms; Nampt could also be secreted by tumor epithelial cells in an autocrine manner. It could stimulate mammary epithelial cell proliferation, invasion, metastasis, and angiogenesis, which is essential for BC development and progression. Serum Nampt might be a novel risk factor as well as a potential diagnostic and prognostic biomarker in PBC. In addition, pharmacologic agents that neutralize biochemically Nampt or medications that decrease Nampt levels or downregulate signaling pathways downstream of Nampt may prove to be useful anti-cancer agents. The potential harmful effect on PBC risk due to vitamin B3 (nicotinic acid, a natural NAD precursor in the biosynthetic route leading to NAD) intake is speculated for the first time. In this hypothesis, the role of Nampt in BC carcinogenesis and progression is explored as well as the pathophysiological mechanisms that underlie the association between Nampt and PBC in the context of a dysfunctional adipose tissue in obesity. Understanding of these mechanisms may be important for the development of preventive and therapeutic strategies against PBC.
全球范围内乳腺癌（BC）是一个严重的公共卫生问题。超重与绝经后乳腺癌（PBC）风险相关。最近的研究表明，肥胖、胰岛素抵抗和血清脂肪因子水平的组合与 PBC 的风险和预后相关。烟酰胺磷酸核糖转移酶（Nampt），也称为内脂素和前 B 细胞集落增强因子，存在于内脏脂肪中，是一种新型的具有细胞因子、生长因子和酶功能的多效性脂肪因子。它在各种代谢和应激反应以及细胞能量代谢中发挥重要作用，特别是 NAD 生物合成。Nampt 具有增殖、抗凋亡、促炎和促血管生成的特性。Nampt 的胰岛素模拟功能仍然是一个有争议的问题。肥胖女性的循环 Nampt 水平升高。此外，与已知的 BC 风险因素、人体测量和代谢参数以及众所周知的脂肪因子的血清浓度无关，PBC 患者的 Nampt 水平明显高于健康对照组。有报道称，BC 组织中 Nampt 的高表达与更恶性的癌症行为和不良预后相关。鉴于 Nampt 的促有丝分裂性及其增殖、抗凋亡和促血管生成特性，提出了一个新的假设，即 Nampt 可能参与 PBC 的病因发病机制，并可能代表超重/肥胖与 PBC 之间缺失的联系。Nampt 可以通过内分泌和旁分泌机制对正常和肿瘤性乳腺组织发挥作用；Nampt 也可以通过肿瘤上皮细胞自分泌的方式分泌。它可以刺激乳腺上皮细胞增殖、侵袭、转移和血管生成，这对 BC 的发展和进展至关重要。血清 Nampt 可能是 PBC 的一个新的危险因素，也是潜在的诊断和预后生物标志物。此外，中和生化 Nampt 的药物或降低 Nampt 水平或下调 Nampt 下游信号通路的药物可能被证明是有用的抗癌药物。首次推测维生素 B3（烟酸，NAD 生物合成途径中的天然 NAD 前体）摄入对 PBC 风险的潜在有害影响。在这个假设中，探索了 Nampt 在 BC 癌变和进展中的作用以及在肥胖中脂肪组织功能障碍的背景下，Nampt 与 PBC 之间的关联所涉及的病理生理机制。对这些机制的理解可能对预防和治疗 PBC 的策略的发展很重要。
