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

Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK.
The EMBO Journal (Impact Factor: 10.43). 06/2011; 30(15):3019-27. DOI: 10.1038/emboj.2011.216
Source: PubMed


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.

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    • "By contrast, in the apocrine breast cancer subtype- an ER negative tumor- the AR acts by binding to the same transcription factors as the ER does, mainly through FOXA1, leading to a luminal gene expression phenotype [8]. In this case the expression of AR is associated with worse prognosis [8]. Recently, using gene expression analyses TNBC has been classified in subtypes including one termed luminal androgen that was enriched in genes related to this pathway [9]. "
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