Ferroportin and Iron Regulation in Breast Cancer Progression and Prognosis
Ferroportin and Iron Regulation in Breast Cancer Progression and Prognosis
复制标题
DOI：
10.1126/scisignal.3001127
复制
发表时间：
2010-08-04
影响因子：
17.1
通讯作者：
Torti, Frank M.
中科院分区：
文献类型：
--
作者：
Pinnix, Zandra K.;Miller, Lance D.;Torti, Frank M.
铁转运蛋白和铁调素是调节全身铁稳态的关键蛋白质。膜铁转运蛋白是唯一已知的输出细胞内非血红素相关铁的机制;其稳定性由激素铁调素调节。虽然ferroportin深刻地影响细胞内铁的浓度在组织中的重要的全身性铁的吸收和运输，ferroportin浓度在乳腺癌及其对生长和预后的影响还没有被检查。我们在这里表明，ferroportin和hepcidin表达在培养的人乳腺上皮细胞和hepcidin调节ferroportin在这些细胞。此外，与非恶性乳腺上皮细胞相比，乳腺癌细胞中的ferroportin蛋白质显著减少; ferroportin蛋白质丰度与代谢可用铁相关。运铁蛋白也存在于正常人乳腺组织中，并且在乳腺癌组织中显著降低，其中最高程度的间变性与最低运铁蛋白表达相关。用膜铁转运蛋白转染乳腺癌细胞显著降低其原位植入小鼠乳腺脂肪垫后的生长。来自>800名女性的乳腺癌基因表达谱显示，ferroportin基因表达降低与无转移和疾病特异性生存率显著降低相关，这与其他乳腺癌风险因素无关。高铁转运蛋白和低铁调素基因表达鉴定了具有> 90%的10年存活率的极其有利的乳腺癌患者队列。膜铁转运蛋白是乳腺生物学中的关键蛋白，也是乳腺癌预后的一个强有力的独立预测因子。
Ferroportin and hepcidin are critical proteins for the regulation of systemic iron homeostasis. Ferroportin is the only known mechanism for export of intracellular non-heme-associated iron; its stability is regulated by the hormone hepcidin. Although ferroportin profoundly affects concentrations of intracellular iron in tissues important for systemic iron absorption and trafficking, ferroportin concentrations in breast cancer and their influence on growth and prognosis have not been examined. We demonstrate here that both ferroportin and hepcidin are expressed in cultured human breast epithelial cells and that hepcidin regulates ferroportin in these cells. Further, ferroportin protein is substantially reduced in breast cancer cells compared to nonmalignant breast epithelial cells; ferroportin protein abundance correlates with metabolically available iron. Ferroportin protein is also present in normal human mammary tissue and markedly decreased in breast cancer tissue, with the highest degree of anaplasia associated with lowest ferroportin expression. Transfection of breast cancer cells with ferroportin significantly reduces their growth after orthotopic implantation in the mouse mammary fat pad. Gene expression profiles in breast cancers from >800 women reveal that decreased ferroportin gene expression is associated with a significant reduction in metastasis-free and disease-specific survival that is independent of other breast cancer risk factors. High ferroportin and low hepcidin gene expression identifies an extremely favorable cohort of breast cancer patients who have a 10-year survival of >90%. Ferroportin is a pivotal protein in breast biology and a strong and independent predictor of prognosis in breast cancer.