The estrogen receptor (ER) drives the majority (>70%) of breast cancers, a feature that requires the forkhead transcription factor FoxA1 to open chromatin for ER to bind DNA. In breast cancers that lack ER, the androgen receptor (AR) has been implicated as an oncogenic driver. In support of this concept, we have previously shown that AR genomically phenocopied ER in associating with FOXA1 and inducing a luminal gene expression profile in ER-negative breast cancer cells (1). Herein, we investigated the consequences of FoxA1 loss on AR signalling in this context. Transient knock-down of FoxA1 in the MDA-MB-453 cell line model inhibited cell proliferation but did not prevent AR from binding to DNA. Rather, the AR cistrome was substantially reprogrammed, with gain of AR binding at a large number of genomic loci. Genome-wide analysis of histone marks associated with active transcription (H3K4me1, H3K27Ac) demonstrated that the “AR reprogrammed” sites were pre-marked before the loss of FoxA1. Quantitative proteomic comparison of the chromatin-bound AR transcriptional complex in the absence of FoxA1 revealed an increased interaction with AP2α, a transcription factor associated with the AR cistrome in mouse epididymis. Stimulation of AR/AP2α interactions by FoxA1 knockdown was validated using proximity ligation assays in the MDA-MB-453 and MFM-223 cell line models. Transient knockdown of AP2α revealed this factor was required for AR to bind to loci associated with FOXA1 loss. Importantly, these AP2α-dependent/FoxA1-independent AR binding sites were associated with genes up-regulated in ER-positive (luminal) compared to more aggressive ER-negative (basal/mesenchymal) breast cancers. Overall, our findings suggest that loss of FoxA1 can result in a switch to AP2α-directed AR signalling, which is associated with reduced proliferative capacity and a more luminal phenotype in ER-negative breast cancers. These findings suggest the oncogenic activity of AR in this disease context may be dependent upon interaction with FOXA1.