Androgen receptor driven transcription in molecular apocrine breast cancer is mediated by FoxA1

• Published in: The EMBO journal 2011-08, Vol.30 (15), p.3019-3027
• Main Authors: Robinson, Jessica L L, MacArthur, Stewart, Ross‐Innes, Caryn S, Tilley, Wayne D, Neal, David E, Mills, Ian G, Carroll, Jason S
• Format: Article
• Language: English
• Subjects: androgen receptor; Androgens; Apocrine Glands - pathology; Binding sites; Breast cancer; Breast Neoplasms - pathology; Cell Line, Tumor; Chromatin; DNA - metabolism; FoxA1; Hepatocyte Nuclear Factor 3-alpha - metabolism; Humans; molecular apocrine; Molecular biology; Promoter Regions, Genetic; Protein Binding; Receptors, Androgen - metabolism; Transcription, Genetic; Tumors
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2011.216

Breast cancer is a heterogeneous disease and several distinct subtypes exist based on differential gene expression patterns. Molecular apocrine tumours were recently identified as an additional subgroup, characterised as oestrogen receptor negative and androgen receptor positive (ER− AR+), but with an expression profile resembling ER+ luminal breast cancer. One possible explanation for the apparent incongruity is that ER gene expression programmes could be recapitulated by AR. Using a cell line model of ER− AR+ molecular apocrine tumours (termed MDA‐MB‐453 cells), we map global AR binding events and find a binding profile that is similar to ER binding in breast cancer cells. We find that AR binding is a near‐perfect subset of FoxA1 binding regions, a level of concordance never previously seen with a nuclear receptor. AR functionality is dependent on FoxA1, since silencing of FoxA1 inhibits AR binding, expression of the majority of the molecular apocrine gene signature and growth cell growth. These findings show that AR binds and regulates ER cis ‐regulatory elements in molecular apocrine tumours, resulting in a transcriptional programme reminiscent of ER‐mediated transcription in luminal breast cancers. This paper explores genome‐wide and functional approaches to reveal that the subgroup of so‐called apocrine breast cancer utilise androgen receptor (AR) binding in the vicinity of oestrogen receptor (ER)‐binding sites to maintain an ER‐like gene expression signature. The results further reveal that FoxA1 is required for AR binding and function.