Coradini Danila
Department of Clinical Sciences and Community Health, Campus Cascina Rosa, University of Milan, 20133 Milan, Italy.
Explor Target Antitumor Ther. 2022;3(6):841-852. doi: 10.37349/etat.2022.00116. Epub 2022 Dec 28.
The onset and development of breast cancer in postmenopausal women are associated with closely related individual-dependent factors, including weight gain and high levels of circulating androgens. Adipose tissue is the most peripheral site of aromatase enzyme synthesis; therefore, the excessive accumulation of visceral fat results in increased androgens aromatization and estradiol production that provides the microenvironment favorable to tumorigenesis in mammary epithelial cells expressing estrogen receptors (ERs). Moreover, to meet the increased requirement of cholesterol for cell membrane assembly and the production of steroid hormones to sustain their proliferation, ER-positive cells activate cholesterol biosynthesis and subsequent steroidogenesis. Several approaches have been followed to neutralize the cholesterol synthesis, including specific enzyme inhibitors, statins, and, more recently, metformin. Cumulating evidence indicated that inhibiting cholesterol biosynthesis by statins and metformin may be a promising therapeutic strategy to block breast cancer progression. Unlike antiestrogens and aromatase inhibitors (AIs) which compete for binding to ER and inhibit androgens aromatization, respectively, statins block the production of mevalonic acid by inhibiting the activity of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, and metformin hampers the activation of the sterol regulatory element-binding protein 2 (SREBP2) transcription factor, thus inhibiting the synthesis of several enzymes involved in cholesterol biosynthesis. Noteworthy, statins and metformin not only improve the prognosis of overweight patients with ER-positive cancer but also improve the prognosis of patients with triple-negative breast cancer, the aggressive tumor subtype that lacks, at present, specific therapy.
绝经后女性乳腺癌的发病和发展与个体相关因素密切相关，包括体重增加和循环雄激素水平升高。脂肪组织是芳香化酶合成的最外周部位；因此，内脏脂肪的过度积累导致雄激素芳香化增加和雌二醇生成，为表达雌激素受体（ERs）的乳腺上皮细胞肿瘤发生提供了有利的微环境。此外，为了满足细胞膜组装对胆固醇增加的需求以及类固醇激素生成以维持其增殖，ER阳性细胞激活胆固醇生物合成及随后的类固醇生成。已经采取了几种方法来中和胆固醇合成，包括特异性酶抑制剂、他汀类药物，以及最近的二甲双胍。越来越多的证据表明，用他汀类药物和二甲双胍抑制胆固醇生物合成可能是阻断乳腺癌进展的一种有前景的治疗策略。与分别竞争与ER结合和抑制雄激素芳香化的抗雌激素和芳香化酶抑制剂（AIs）不同，他汀类药物通过抑制3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶的活性来阻断甲羟戊酸的产生，而二甲双胍则阻碍固醇调节元件结合蛋白2（SREBP2）转录因子的激活，从而抑制参与胆固醇生物合成的几种酶的合成。值得注意的是，他汀类药物和二甲双胍不仅改善了ER阳性癌症超重患者的预后，还改善了三阴性乳腺癌患者的预后，三阴性乳腺癌是一种目前缺乏特异性治疗的侵袭性肿瘤亚型。
