SRP384925 PRJNA855897 GSE207472 AP-2ß activates enhancers that define mammary hormone sensing cell identity [RNA-seq] The Activating Protein 2ß transcription factor (TFAP2B; AP-2ß) is a marker for both lobular and molecular apocrine/HER2-E breast cancers, despite these tumours having very different prognoses. We show that simultaneous expression of both AP-2ß and the estrogen receptor (ESR1, ER) marks well differentiated, low proliferation cells that are characteristic of luminal A lobular tumours, but loss of ER expression occurs when the tumour cells progress to molecular apocrine tumours. To discover potential explanations for this behaviour we performed chromatin immunoprecipitation sequencing (ChIP-seq) for AP-2ß, AR, GATA3, FOXA1 and H3K27 acetylation in ER-negative MDA-MB-453 breast cancer cells. We find that all four transcription factors frequently bind to the same enhancers and that these enhancers are more likely to be active when AP-2ß is present. Molecular apocrine genes are significantly more likely to have enhancers bound to all four transcription factors flanked by H3K27 acetylation. When AP-2ß binds separately from the other factors, it binds close to the transcription start site, where it shows very high enrichment for H3K27 acetylation. AP-2 family proteins activate transcription by recruiting CITED proteins and p300/CBP. Since AR, FOXA1 and GATA3 are themselves able to recruit histone acetyl-transferases, we infer that AP-2ß regulates the activity of those histone acetyl-transferases. We propose that this broad fundamental role in transcription explains the contradictory functions, both oncogenic and tumour suppressing, that have been assigned to AP-2 family members in previous studies on cancer. Overall design: RNA-seq (poly-A) in MDA-MB-453 cells GSE207472 parent_bioproject PRJNA855883