Sanders Deborah A, Ross-Innes Caryn S, Beraldi Dario, Carroll Jason S, Balasubramanian Shankar
Genome Biol. 2013 Jan 24;14(1):R6. doi: 10.1186/gb-2013-14-1-r6.
The forkhead transcription factor FOXM1 is a key regulator of the cell cycle. It is frequently over-expressed in cancer and is emerging as an important therapeutic target. In breast cancer FOXM1 expression is linked with estrogen receptor (ERα) activity and resistance to endocrine therapies, with high levels correlated with poor prognosis. However, the precise role of FOXM1 in ER positive breast cancer is not yet fully understood.
The study utilizes chromatin immunoprecipitation followed by high-throughput sequencing to map FOXM1 binding in both ERα-positive and -negative breast cancer cell lines. The comparison between binding site distributions in the two cell lines uncovered a previously undescribed relationship between binding of FOXM1 and ERα. Further molecular analyses demonstrated that these two factors can bind simultaneously at genomic sites and furthermore that FOXM1 regulates the transcriptional activity of ERα via interaction with the coactivator CARM1. Inhibition of FOXM1 activity using the natural product thiostrepton revealed down-regulation of a set of FOXM1-regulated genes that are correlated with patient outcome in clinical breast cancer samples.
These findings reveal a novel role for FOXM1 in ERα transcriptional activity in breast cancer and uncover a FOXM1-regulated gene signature associated with ER-positive breast cancer patient prognosis.
叉头转录因子FOXM1是细胞周期的关键调节因子。它在癌症中经常过度表达，并逐渐成为一个重要的治疗靶点。在乳腺癌中，FOXM1的表达与雌激素受体（ERα）活性及内分泌治疗耐药性相关，高水平表达与不良预后相关。然而，FOXM1在雌激素受体阳性乳腺癌中的确切作用尚未完全明确。
该研究利用染色质免疫沉淀结合高通量测序技术，绘制了雌激素受体α阳性和阴性乳腺癌细胞系中FOXM1的结合图谱。两种细胞系中结合位点分布的比较揭示了FOXM1与ERα结合之间一种前所未有的关系。进一步的分子分析表明，这两个因子可在基因组位点同时结合，而且FOXM1通过与共激活因子CARM1相互作用来调节ERα的转录活性。使用天然产物硫链丝菌素抑制FOXM1活性，发现一组FOXM1调节的基因表达下调，这些基因与临床乳腺癌样本中的患者预后相关。
这些发现揭示了FOXM1在乳腺癌雌激素受体α转录活性中的新作用，并发现了一个与雌激素受体阳性乳腺癌患者预后相关的FOXM1调节基因特征。
