McDonnell D P, Chang C-Y, Nelson E R
Department of Pharmacology and Cancer Biology, Duke University School of Medicine , Durham, NC , USA.
Climacteric. 2014 Dec;17 Suppl 2(0 2):60-5. doi: 10.3109/13697137.2014.966949. Epub 2014 Oct 16.
Despite increased survivorship among patients, breast cancer remains the most common cancer among women and is the second leading cause of cancer death in women. The magnitude of this problem provides a strong impetus for new chemopreventative strategies and/or lifestyle changes that reduce cancer incidence. It is of significance, therefore, that several studies positively correlate obesity to the development of breast cancer. Importantly, obesity is also highly associated with elevated cholesterol, and cholesterol itself is a risk factor for breast cancer. Furthermore, patients taking statins demonstrate a lower breast cancer incidence and decreased recurrence. The recent observation that 27-hydroxycholesterol (27HC) is produced in a stoichiometric manner from cholesterol, together with our recent demonstration that it exerts partial agonist activity on both the estrogen and liver X receptors, suggested a potential mechanistic link between hyper-cholesterolemia and breast cancer incidence. Using genetic and pharmacological approaches, we have recently shown that elevation of circulating 27HC significantly increases tumor growth and metastasis in murine models of breast cancer. Further, we have demonstrated in appropriate animal models that the impact of high-fat diet on tumor pathogenesis can be mitigated by statins or by small molecule inhibitors of CYP27A1. These findings suggest that pharmacological or dietary modifications that lower total cholesterol, and by inference 27HC, are likely to reduce the impact of obesity/metabolic syndrome on breast cancer incidence.
尽管患者的生存率有所提高，但乳腺癌仍是女性中最常见的癌症，并且是女性癌症死亡的第二大主要原因。这一问题的严重性为降低癌症发病率的新化学预防策略和/或生活方式改变提供了强大动力。因此，多项研究表明肥胖与乳腺癌的发生呈正相关，这一点具有重要意义。重要的是，肥胖还与胆固醇升高高度相关，而胆固醇本身就是乳腺癌的一个风险因素。此外，服用他汀类药物的患者乳腺癌发病率较低且复发率降低。最近观察到27-羟基胆固醇（27HC）以化学计量方式由胆固醇产生，以及我们最近证明它对雌激素受体和肝脏X受体均具有部分激动剂活性，这提示了高胆固醇血症与乳腺癌发病率之间潜在的机制联系。我们最近使用遗传和药理学方法表明，循环中27HC的升高会显著增加乳腺癌小鼠模型中的肿瘤生长和转移。此外，我们在合适的动物模型中证明，高脂饮食对肿瘤发病机制的影响可通过他汀类药物或CYP27A1小分子抑制剂来减轻。这些发现表明，降低总胆固醇（由此推断也降低27HC）的药理学或饮食调整可能会减少肥胖/代谢综合征对乳腺癌发病率的影响。
