Association of Double-Positive FOXA1 and FOXP1 Immunoreactivities with Favorable Prognosis of Tamoxifen-Treated Breast Cancer Patients
Association of Double-Positive FOXA1 and FOXP1 Immunoreactivities with Favorable Prognosis of Tamoxifen-Treated Breast Cancer Patients
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DOI：
10.1007/s12672-012-0111-0
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发表时间：
2012-08-01
影响因子：
3
通讯作者：
Inoue, Satoshi
中科院分区：
文献类型：
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作者：
Ijichi, Nobuhiro;Shigekawa, Takashi;Inoue, Satoshi
乳腺癌主要是一种激素依赖型肿瘤，可以通过类固醇激素雌激素和孕激素的状态进行调节。叉头盒A1(Forkhead box A1，FOXA1)是叉头盒转录因子家族的一员，是乳腺癌雌激素受体(ER)的先驱因子。在本研究中，我们证明了雌激素上调了FOXA1基因的表达，并且在雌激素α阳性的MCF-7乳腺癌细胞中，雌激素促进了雌激素受体α(ERα)在FOXA1基因附近的ER结合部位的募集。4-羟基他莫昔芬可抑制雌激素诱导的FOXA1上调。我们还发现，FOXA1特异性的小干扰RNA(siRNA；siFOXA1)可以抑制MCF-7细胞的增殖和迁移。此外，siFOXA1降低了雌激素反应元件驱动的转录和雌激素依赖性的ERα靶基因的上调。接下来，对两组乳腺癌标本进行FOXA1的免疫组织化学分析。在108例浸润性乳腺癌中，有80例(74%)检测到FOXA1的核免疫反应，其表达与肿瘤分级呈负相关，与激素受体状态呈正相关，包括ERα和孕激素受体、病理肿瘤大小和另一Fox家族转录因子Foxp1的免疫反应。在接受三苯氧胺治疗的无复发乳腺癌患者中，FOXA1免疫反应性显著升高。值得注意的是，FOXA1和Foxp1的双重阳性免疫反应与接受他莫昔芬治疗的乳腺癌患者的无复发和总存活率的良好预后显著相关，与FOXA1或Foxp1单独免疫反应相比，P值更低。这些结果提示FOXA1通过调节雌激素信号在乳腺癌细胞的增殖和迁移中起重要作用，FOXA1和Foxp1的双阳性免疫反应与三苯氧胺治疗乳腺癌的良好预后有关。
Breast cancer is primarily a hormone-dependent tumor that can be regulated by the status of the steroid hormones estrogen and progesterone. Forkhead box A1 (FOXA1) is a member of the forkhead box transcription factor family and functions as a pioneer factor of the estrogen receptor (ER) in breast cancer. In the present study, we demonstrate that FOXA1 mRNA was upregulated by estrogen and that estrogen receptor-alpha (ER alpha) recruitment to ER-binding sites in the vicinity of the FOXA1 gene was increased by estrogen in ER alpha-positive MCF-7 breast cancer cells. The estrogen-induced FOXA1 upregulation was repressed by 4-hydroxytamoxifen treatment. We also demonstrated that the proliferation and the migration of MCF-7 cells were decreased by FOXA1-specific small interfering RNA (siRNA; siFOXA1). Furthermore, siFOXA1 decreased the estrogen response element-driven transcription and the estrogen-dependent upregulation of ER alpha target genes in MCF-7 cells. Next, the immunohistochemical analyses of FOXA1 were performed using two groups of breast cancer specimens. The nuclear immunoreactivity of FOXA1 was detected in 80 (74 %) of 108 human invasive breast cancers and was negatively correlated with tumor grade and positively correlated with hormone receptor status, including ER alpha and progesterone receptor, pathological tumor size, and immunoreactivity of FOXP1, another FOX family transcription factor. FOXA1 immunoreactivity was significantly elevated in the relapse-free breast cancer patients treated with tamoxifen. Notably, the double-positive immunoreactivities of FOXA1 and FOXP1 were significantly associated with a favorable prognosis for the relapse-free and overall survival of patients with tamoxifen-treated breast cancer, with lower P values compared with FOXA1 or FOXP1 immunoreactivity alone. These results suggest that FOXA1 plays an important role in the proliferation and migration of breast cancer cells by modulating estrogen signaling and that the double-positive immunoreactivities of FOXA1 and FOXP1 are associated with a favorable prognosis of tamoxifen-treated breast cancer.