Progesterone receptor inhibits aromatase and inflammatory response pathways in breast cancer cells via ligand-dependent and ligand-independent mechanisms
Progesterone receptor inhibits aromatase and inflammatory response pathways in breast cancer cells via ligand-dependent and ligand-independent mechanisms
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DOI：
10.1210/me.2007-0443
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发表时间：
2008-08-01
影响因子：
--
通讯作者：
Mendelson, Carole R.
中科院分区：
文献类型：
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作者：
Hardy, Daniel B.;Janowski, Bethany A.;Mendelson, Carole R.
芳香化酶（CYP 19基因的产物）是雌激素生物合成中的关键酶，在所有乳腺癌中70%上调，并且与前列腺素类生物合成中的速率决定酶环氧合酶2（考克斯-2）高度相关。考克斯-2的表达也与癌基因HER-2/neu相关。只有当肿瘤含有大量雌激素受体时，才能预测当前乳腺癌内分泌疗法的疗效。由于孕激素受体（PR）是雌激素诱导的靶基因，因此已提出其存在可作为雌激素受体功能能力和肿瘤分化状态的指标。在本研究中，我们测试了这一假设，即PR通过拮抗乳腺炎性反应途径发挥重要的保护作用。我们观察到孕酮拮抗cAMP和IL-1 β对T47 D乳腺癌细胞芳香化酶、考克斯-2和HER-2/neu表达的刺激作用。孕酮的这些作用与核因子-κ B抑制剂I κ B α的表达增加有关。在28个乳腺癌细胞系中，I κ B α表达与PR mRNA水平呈正相关; I κ B α磷酸化缺陷突变体的过表达抑制芳香化酶、考克斯-2和HER-2/neu的表达。此外，在孕激素不存在的情况下培养的乳腺癌细胞系中，内源性PR的上调导致芳香化酶、考克斯-2和HER-2/neu表达的降低，而内源性PR的下调导致芳香化酶和HER 2/neu mRNA的显著诱导。总的来说，这些发现表明PR通过配体依赖性和配体非依赖性机制在乳腺癌细胞中发挥重要的促增殖作用。
Aromatase (product of CYP19 gene), the critical enzyme in estrogen biosynthesis, is up- regulated in 70% of all breast cancers and is highly correlated with cyclooxygenase 2 (COX-2), the rate-determining enzyme in prostanoid biosynthesis. Expression of COX-2 also is correlated with the oncogene HER-2/neu. The efficacy of current endocrine therapies for breast cancer is predicted only if the tumor contains significant amounts of estrogen receptor. Because the progesterone receptor (PR) is an estrogen- induced target gene, it has been suggested that its presence may serve as an indicator of estrogen receptor functional capacity and the differentiation state of the tumor. In the present study, we tested the hypothesis that PR serves a crucial protective role by antagonizing inflammatory response pathways in the breast. We observed that progesterone antagonized the stimulatory effects of cAMP and IL-1 beta on aromatase, COX-2, and HER-2/neu expression in T47D breast cancer cells. These actions of progesterone were associated with increased expression of the nuclear factor-kappa B inhibitor, I kappa B alpha. In 28 breast cancer cell lines, I kappa B alpha expression was positively correlated with PR mRNA levels; overexpression of a phosphorylation-defective mutant of I kappa B alpha inhibited expression of aromatase, COX-2, and HER-2/neu. Moreover, in breast cancer cell lines cultured in the absence of progesterone, up-regulation of endogenous PR caused decreased expression of aromatase, COX-2, and HER-2/neu expression, whereas down-regulation of endogenous PR resulted in a marked induction of aromatase and HER2/neu mRNA. Collectively, these findings suggest that PR plays an important antiinflammatory role in breast cancer cells via ligand-dependent and ligand-independent mechanisms.