IGFs & Metabolic Endocrinology Group, Translational Health Sciences, Bristol Medical School, Learning & Research Building, Southmead Hospital, Bristol BS10 5NB, UK.
Cells. 2021 Dec 29;11(1):94. doi: 10.3390/cells11010094.
Cholesterol-in particular, high levels of low-density lipoprotein (LDL) and its metabolite, 27-hydroxycholesterol (27-OHC)-is correlated with increases in the risks of breast cancer and obesity. Although the high expression of LDL/27-OHC has been reported in breast cancer, its effects and mechanism of action remain to be fully elucidated. In this study, we found that the effects of LDL on cell proliferation were mediated by the activation of the cytochrome P450 enzyme, sterol 27 hydroxylase, and cholesterol 27-hydroxylase (CYP27A1) in both ER-α-positive and ER-α-negative breast cancer cells. We found that treatment with 27-OHC only increased cell growth in oestrogen receptor-α (ER-α)-positive breast cancer cells in an ER-α-dependent manner, but, interestingly, the effects of 27-OHC on cell migration and invasion were independent of ER-α. Using ER-α-negative MDA-MB-231 cells, we found that 27-OHC similarly promoted cell invasion and migration, and this was mediated by oestrogen receptor β (ER-β). These results suggest that 27-OHC promotes breast cancer cell proliferation in ER-α-positive breast cancer cells via ER-α, but migration and invasion are mediated via ER-β in ER-α positive and negative cell lines. The addition of LDL/27OHC increased the production of IGF-I and the abundance of IGF-IR in TNBC. We further found that modulating ER-β using an agonist or antagonist increased or decreased, respectively, levels of the IGF-I and EGF receptors in TNBC. The inhibition of the insulin-like growth factor receptor blocked the effects of cholesterol on cell growth and the migration of TNBC. Using TCGA and METABRIC microarray expression data from invasive breast cancer carcinomas, we also observed that higher levels of ER-beta were associated with higher levels of IGF-IR. Thus, this study shows novel evidence that ER-β is central to the effects of LDL/27OHC on invasion, migration, and the IGF and EGF axes. Our data suggest that targeting ER-β in TNBC could be an alternative approach for downregulating IGF/EGF signalling and controlling the impact of LDL in breast cancer patients.
胆固醇——尤其是低密度脂蛋白（LDL）及其代谢产物 27-羟胆固醇（27-OHC）——与乳腺癌和肥胖风险的增加有关。虽然已经报道 LDL/27-OHC 在乳腺癌中高表达，但其作用和作用机制仍有待充分阐明。在这项研究中，我们发现 LDL 对细胞增殖的影响是通过细胞色素 P450 酶、固醇 27-羟化酶和胆固醇 27-羟化酶（CYP27A1）在 ER-α 阳性和 ER-α 阴性乳腺癌细胞中的激活介导的。我们发现，27-OHC 处理仅以 ER-α 依赖的方式增加雌激素受体-α（ER-α）阳性乳腺癌细胞的细胞生长，但有趣的是，27-OHC 对细胞迁移和侵袭的影响与 ER-α 无关。使用 ER-α 阴性 MDA-MB-231 细胞，我们发现 27-OHC 同样促进细胞侵袭和迁移，这是由雌激素受体β（ER-β）介导的。这些结果表明，27-OHC 通过 ER-α 促进 ER-α 阳性乳腺癌细胞的增殖，但迁移和侵袭则通过 ER-α 阳性和阴性细胞系中的 ER-β 介导。LDL/27OHC 的添加增加了 TNBC 中 IGF-I 的产生和 IGF-IR 的丰度。我们进一步发现，使用激动剂或拮抗剂调节 ER-β 分别增加或减少了 TNBC 中 IGF-I 和 EGF 受体的水平。胰岛素样生长因子受体的抑制阻断了胆固醇对 TNBC 细胞生长和迁移的影响。使用 TCGA 和 METABRIC 微阵列表达数据从浸润性乳腺癌中，我们还观察到 ER-β 水平较高与 IGF-IR 水平较高相关。因此，这项研究提供了新的证据，表明 ER-β 是 LDL/27OHC 对侵袭、迁移以及 IGF 和 EGF 轴影响的核心。我们的数据表明，在 TNBC 中靶向 ER-β 可能是下调 IGF/EGF 信号和控制 LDL 在乳腺癌患者中影响的另一种方法。
