Vona-Davis Linda, Rose David P
Department of Surgery and Breast Cancer Research Program, Mary Babb Randolph Cancer Center, West Virginia University Robert C. Byrd Health Sciences Center, P.O. Box 9238, Morgantown, WV 26506, USA.
Curr Diabetes Rev. 2012 Mar;8(2):116-30. doi: 10.2174/157339912799424519.
The objective was to review type 2 diabetes as a risk factor for breast cancer, its influence on tumor aggressiveness and prognosis, and the interactions with obesity. Consideration was given to the responsible biological mechanisms and how these relate to the potential of hypoglycemic agents, notably metformin, as breast cancer chemotherapeutic agents. Most epidemiological studies indicate that type 2 diabetes is a modest positive risk factor for postmenopausal, but not premenopausal, breast cancer; indeed before the menopause it may be associated with a reduced risk. This pattern of differing effects on risk according to menopausal status is well established in obesity; however, although most type 2 diabetics are obese, the relationship with postmenopausal breast cancer does not appear to be a function of the body mass index. We suggest that before menopause the protective effect of obesity may modify any adverse effects of the metabolic changes related to type 2 diabetes. Regardless of menopausal status, obesity is associated with breast cancers that exhibit aggressive biological characteristics at the time of diagnosis and have a poor prognosis; a similar relationship is emerging for type 2 diabetes. The two metabolic disorders share biological mechanisms for their associations with breast cancer, including a direct effect of insulin on breast cancer cell proliferation, increased extraglandular estrogen production and bioavailability, changes in the adipokines, notably adiponectin, and activation of the AMP-activated protein kinase pathway. These mechanistic considerations are consistent with metformin having high potential as a breast cancer chemopreventive and therapeutic agent.
目的是综述2型糖尿病作为乳腺癌的危险因素、其对肿瘤侵袭性和预后的影响以及与肥胖的相互作用。研究了相关的生物学机制以及这些机制与降糖药物（尤其是二甲双胍）作为乳腺癌化疗药物潜力的关系。大多数流行病学研究表明，2型糖尿病是绝经后乳腺癌的一个适度的阳性危险因素，但不是绝经前乳腺癌的危险因素；实际上，在绝经前，它可能与风险降低有关。肥胖症中，根据绝经状态对风险产生不同影响的这种模式已得到充分证实；然而，尽管大多数2型糖尿病患者肥胖，但与绝经后乳腺癌的关系似乎不是体重指数的函数。我们认为，在绝经前，肥胖的保护作用可能会改变与2型糖尿病相关的代谢变化的任何不良影响。无论绝经状态如何，肥胖都与诊断时具有侵袭性生物学特征且预后不良的乳腺癌相关；2型糖尿病也出现了类似的关系。这两种代谢紊乱与乳腺癌相关的生物学机制相同，包括胰岛素对乳腺癌细胞增殖的直接作用、腺体外雌激素产生和生物利用度增加、脂肪因子（尤其是脂联素）的变化以及AMP激活的蛋白激酶途径的激活。这些机制上的考虑与二甲双胍作为乳腺癌化学预防和治疗药物具有很高潜力是一致的。
