FOXA1 as a therapeutic target for breast cancer

Gene expression profiling studies have classified breast cancer into five intrinsic subtypes with distinct prognostic significance: luminal type A, luminal type B, normal-like, HER-2-positive and basal type. These studies have also uncovered novel diagnostic markers and molecular targets. FOXA1, a winged-helix transcription factor belonging to the forkhead family, is one among them as it is expressed predominantly in luminal type A breast cancer, which is characterized by the presence of estrogen receptor-alpha (ERalpha) with favorable prognosis. FOXA1 is a 'pioneer' factor that binds to chromatinized DNA, opens the chromatin and enhances binding of ERalpha to its target genes. It is essential for the expression of approximately 50% of ERalpha:estrogen-regulated genes. Thus, a network comprising FOXA1, ERalpha and estrogen constitutes a major proliferation and survival signal for luminal type A breast cancer. However, by controlling differentiation and by regulating the expression of cell cycle inhibitor p27kip1 and the cell adhesion molecule E-cadherin, FOXA1 may prevent metastatic progression of luminal type A breast cancer. This article reviews possible roles of FOXA family transcription factors in breast cancer initiation, hormone dependency and speculates on the potential of FOXA1 as a therapeutic target.