Terminal differentiation of human breast cancer through PPARγ
Terminal differentiation of human breast cancer through PPARγ
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DOI：
10.1016/s1097-2765(00)80047-7
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发表时间：
1998-02-01
期刊：
影响因子：
16
通讯作者：
Spiegelman, BM
中科院分区：
文献类型：
--
作者：
Mueller, E;Sarraf, P;Spiegelman, BM
我们以前已经证明，当被合成配体激活时，如抗糖尿病噻唑烷二酮（TZD）药物，PPAR γ刺激脂肪细胞前体的终末分化。我们在这里表明，在人类原发性和转移性乳腺腺癌中，过氧化物酶体增殖物激活受体γ的表达水平显着。这种受体在培养的乳腺癌细胞中的配体活化引起广泛的脂质积累，与更分化、更少恶性状态相关的乳腺上皮基因表达的变化，以及细胞生长速率和克隆形成能力的降低。MAP激酶的抑制，以前被证明是一个强大的负性调节剂的过氧化物酶体增殖物激活受体γ，提高TZD配体敏感性的无反应细胞。这些数据表明，过氧化物酶体增殖物激活受体γ转录途径可以诱导恶性乳腺上皮细胞的终末分化，从而可能为人类乳腺癌提供一种新的，无毒的治疗。
We have previously demonstrated that PPAR gamma stimulates the terminal differentiation of adipocyte precursors when activated by synthetic ligands, such as the antidiabetic thiazolidinedione (TZD) drugs. We show here that PPAR gamma is expressed at significant levels in human primary and metastatic breast adenocarcinomas. Ligand activation of this receptor in cultured breast cancer cells causes extensive lipid accumulation, changes in breast epithelial gene expression associated with a more differentiated, less malignant state, and a reduction in growth rate and clonogenic capacity of the cells. Inhibition of MAP kinase, shown previously to be a powerful negative regulator of PPAR gamma, improves the TZD ligand sensitivity of nonresponsive cells. These data suggest that the PPAR gamma transcriptional pathway can induce terminal differentiation of malignant breast epithelial cells and thus may provide a novel, nontoxic therapy for human breast cancer.