Lo Pang-Kuo, Lee Ji Shin, Liang Xiaohui, Sukumar Saraswati
Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Cell Signal. 2016 Oct;28(10):1502-19. doi: 10.1016/j.cellsig.2016.06.021. Epub 2016 Jul 1.
Dysregulation of Forkhead-box (FOX) transcription factors is linked to cancers of numerous tissue types. Here, we report that FOXF2 is frequently silenced in luminal-type and HER2-positive breast cancers, but is overexpressed in basal-like breast cancers; thus, FOXF2 appears to play distinct roles in different breast cancer subtypes. Inactivation of FOXF2 in luminal-type and HER2-positive breast cancers is attributable to epigenetic silencing. Silencing of FOXF2 is associated with poor prognosis in luminal-type breast cancer. Ectopic expression of FOXF2 in luminal and HER2-positive breast cancer cells suppresses their tumorigenic properties in vitro and in vivo via inhibition of the CDK2-RB-E2F cascade. The in vivo function of FOXF2 is to maintain the stringency of DNA replication, and its loss triggers dysregulation of DNA replication, which in turn activates the p53 checkpoint pathway. Besides its role in cell cycle regulation, FOXF2 is functionally required for mobility and epithelial-to-mesenchymal transition (EMT) of normal breast epithelial cells. In basal-like breast cancer cells, the cell-cycle function of FOXF2 is impaired. However, the EMT function of FOXF2 is still required for mobility, invasiveness and anchorage-independent growth of basal-like breast cancer cells. Our gene expression profiling studies demonstrate that FOXF2 regulates the expression of genes implicated in cell cycle and EMT regulation. Moreover, FOXF2 is highly co-expressed with basal- and metastasis-related genes in breast cancer. These findings suggest that FOXF2 has a dual role in breast tumorigenesis and functions as either a tumor suppressor or an oncogene depending on the breast tumor subtype.
叉头框（FOX）转录因子的失调与多种组织类型的癌症相关。在此，我们报告FOXF2在管腔型和HER2阳性乳腺癌中经常沉默，但在基底样乳腺癌中过表达；因此，FOXF2似乎在不同的乳腺癌亚型中发挥着不同的作用。管腔型和HER2阳性乳腺癌中FOXF2的失活归因于表观遗传沉默。FOXF2的沉默与管腔型乳腺癌的预后不良相关。FOXF2在管腔型和HER2阳性乳腺癌细胞中的异位表达通过抑制CDK2-RB-E2F级联反应在体外和体内抑制其致瘤特性。FOXF2的体内功能是维持DNA复制的严格性，其缺失会引发DNA复制失调，进而激活p53检查点通路。除了在细胞周期调控中的作用外，FOXF2对于正常乳腺上皮细胞的迁移和上皮-间质转化（EMT）在功能上也是必需的。在基底样乳腺癌细胞中，FOXF2的细胞周期功能受损。然而，FOXF2的EMT功能对于基底样乳腺癌细胞的迁移、侵袭和非锚定依赖性生长仍然是必需的。我们的基因表达谱研究表明，FOXF2调节与细胞周期和EMT调控相关的基因表达。此外，FOXF2在乳腺癌中与基底和转移相关基因高度共表达。这些发现表明，FOXF2在乳腺肿瘤发生中具有双重作用，并根据乳腺肿瘤亚型发挥肿瘤抑制因子或癌基因的作用。
