Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
Horm Cancer. 2012 Aug;3(4):147-59. doi: 10.1007/s12672-012-0111-0. Epub 2012 Apr 3.
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-α (ERα) recruitment to ER-binding sites in the vicinity of the FOXA1 gene was increased by estrogen in ERα-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 ERα 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 ERα 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.
乳腺癌主要是一种激素依赖性肿瘤，可以通过甾体激素雌激素和孕激素的状态来调节。叉头框转录因子 A1（FOXA1）是叉头框转录因子家族的一员，在乳腺癌中作为雌激素受体（ER）的先驱因子发挥作用。在本研究中，我们证明雌激素上调 FOXA1 mRNA 的表达，并且雌激素增加 ERα 阳性 MCF-7 乳腺癌细胞中 FOXA1 基因附近 ER 结合位点处的 ERα 募集。雌激素诱导的 FOXA1 上调被 4-羟基他莫昔芬处理抑制。我们还证明 FOXA1 特异性小干扰 RNA（siRNA；siFOXA1）降低 MCF-7 细胞的增殖和迁移。此外，siFOXA1 降低 MCF-7 细胞中雌激素反应元件驱动的转录和雌激素依赖性 ERα 靶基因的上调。接下来，使用两组乳腺癌标本进行 FOXA1 的免疫组织化学分析。FOXA1 的核免疫反应性在 108 例人类浸润性乳腺癌中的 80 例（74%）中被检测到，并且与肿瘤分级呈负相关，与激素受体状态（包括 ERα 和孕激素受体）、病理肿瘤大小和另一个 FOX 家族转录因子 FOXP1 的免疫反应性呈正相关。FOXA1 免疫反应性在接受他莫昔芬治疗的无复发生存期乳腺癌患者中显著升高。值得注意的是，FOXA1 和 FOXP1 的双重阳性免疫反应性与接受他莫昔芬治疗的乳腺癌患者的无复发生存期和总生存期的良好预后显著相关，与 FOXA1 或 FOXP1 免疫反应性单独相比，具有更低的 P 值。这些结果表明，FOXA1 通过调节雌激素信号转导在乳腺癌细胞的增殖和迁移中发挥重要作用，并且 FOXA1 和 FOXP1 的双重阳性免疫反应性与接受他莫昔芬治疗的乳腺癌的良好预后相关。
