FOXP1: a potential therapeutic target in cancer

Abstract

Forkhead Box P1 (FOXP1) is a member of the FOX family of transcription factors which have a broad range of functions. Foxp1 is widely expressed and has been shown to have a role in cardiac, lung and lymphocyte development. FOXP1 is targeted by recurrent chromosome translocations and its overexpression confers a poor prognosis in a number of types of lymphomas, suggesting it may function as an oncogene. In contrast, FOXP1 localises to a tumour suppressor locus at 3p14.1 and loss of FOXP1 expression in breast cancer is associated with a worse outcome, suggesting FOXP1 may function as a tumour suppressor in other tissue types. These data suggest that FOXP1 may not only be useful in prognosis but also may be used to develop FOXP1-directed therapeutic strategies.

Figure 1. FOXP forkhead domains and NFAT-contacting residues

Upper, schematic secondary structure of the FOXP1 forkhead domain. H1, H2, H3 denote alpha-helix regions; S1, S2, S3 represent beta-strands; W1: the wing domain Lower, alignment of FOXP1-3 with NFAT-binding and DNA-binding residues indicated in green and violet, respectively. Adapted and reprinted from [34] by permission from Elsevier Publishing, Ltd, London. NFAT: Nuclear factor of activated T cells.

Figure 2. FOXP1 expression in ABC-DLBCL

FOXP1 overexpression is a diagnostic genetic marker that has been used to categorise the activated B-cell-like subtype of diffuse large B-cell lymphoma (ABC-DLBCL). Microarray technology was used to determine gene-expression profiles of normal B cells as well as several types of mature B-cell lymphomas. The data is depicted as a “heat map” wherein the color red represents a high relative level of gene expression (RNA transcription), the color green represents a low relative level of gene expression, and black represents an average baseline expression. Each column denotes an individual RNA sample derived from either a normal B-cell patient sample or a malignant B-cell tumour. Each row denotes the expression of a single gene. A 16-fold range of gene expression is shown. Indicated is a subset of genes differentially expressed in GC B cells of secondary lymphoid follicles when compared to mitogenically activated B-cells derived from peripheral blood. The genes CD10, JAW1, and BCL6, for example, seem to define an essential GC B-cell gene-expression signature, which is shared by some lymphomas – namely, follicular lymphoma, Burkitt’s lymphoma, and the GC B-cell-like subset of diffuse large B-cell lymphoma (GC-DLBCL). In contrast, the genes CD44, Cyclin D2, IRF4, and FOXP1 – which are expressed at a higher relative level in mitogenically activated peripheral-blood B cells than in GC B cells – uniquely identify the ABC-like DLBCL subgroup. Adapted from [61] with permission from Macmillan Publishers Ltd. DLBLC: Diffuse large B-cell lymphoma; GC: Germinal centre.