Department of Surgery, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, 26506, USA.
Endocr Relat Cancer. 2012 Nov 9;19(6):R225-41. doi: 10.1530/ERC-12-0203. Print 2012 Dec.
Epidemiological studies have related hyperinsulinemia and type 2 diabetes to an increased breast cancer risk, an aggressive and metastatic phenotype, and a poor prognosis. Furthermore, diabetic retinopathy arises from pathological angiogenesis, which is also essential for breast cancer growth and metastasis. Insulin stimulates the proliferation of some human breast cancer cell lines in vitro by mechanisms that use both the phosphatidylinositol-3 kinase and the mitogen-activated protein kinase/Akt signaling pathways; it is also a cell survival (anti-apoptotic) agent and enhances tumor cell migration and invasive capacity. Hyperinsulinemia affects breast cancer cells via the endocrine system, but experimental studies suggest the importance of paracrine mechanisms operating by the effects of insulin on the secretion of adipokines from tumor-associated adipose tissue. In such a system, one adipokine, leptin, has stimulatory paracrine effects on breast cancer cell proliferation and survival, while a second, adiponectin, is inhibitory. Leptin, vascular endothelial growth factor, another insulin-regulated adipokine, and insulin itself also stimulate angiogenesis. Insulin has complex interactions with estrogens: it induces adipose stromal cell aromatase and tumor cell sex steroid hormone receptor expression and suppresses sex hormone-binding globulin, which may enhance estrogen synthesis and bioactivity with consequent promotion of estrogen-dependent breast cancer. All these actions influence the later steps in breast cancer development but genetic studies are also revealing connections between gene abnormalities related to type 2 diabetes and the initiation stage of breast carcinogenesis. Understanding the various mechanisms by which insulin participates in breast cancer cell biology provides opportunities for novel approaches to treatment.
流行病学研究表明，高胰岛素血症和 2 型糖尿病与乳腺癌风险增加、侵袭性和转移性表型以及预后不良有关。此外，糖尿病视网膜病变源于病理性血管生成，而这对乳腺癌的生长和转移也是必不可少的。胰岛素通过使用磷脂酰肌醇-3 激酶和丝裂原活化蛋白激酶/Akt 信号通路的机制，刺激一些人乳腺癌细胞系在体外增殖；它也是一种细胞存活（抗凋亡）剂，并增强肿瘤细胞迁移和侵袭能力。高胰岛素血症通过内分泌系统影响乳腺癌细胞，但实验研究表明，胰岛素对肿瘤相关脂肪组织中脂肪因子分泌的旁分泌机制的重要性。在这样的系统中，一种脂肪因子瘦素对乳腺癌细胞增殖和存活具有刺激旁分泌作用，而另一种脂肪因子脂联素则具有抑制作用。瘦素、血管内皮生长因子，另一种受胰岛素调节的脂肪因子，以及胰岛素本身也能刺激血管生成。胰岛素与雌激素有复杂的相互作用：它诱导脂肪基质细胞芳香酶和肿瘤细胞性激素受体的表达，并抑制性激素结合球蛋白，这可能增强雌激素的合成和生物活性，从而促进雌激素依赖性乳腺癌。所有这些作用都影响乳腺癌发展的后期步骤，但遗传研究也揭示了与 2 型糖尿病相关的基因异常与乳腺癌起始阶段之间的联系。了解胰岛素参与乳腺癌细胞生物学的各种机制为治疗提供了新的机会。
