Androgen receptor driven transcription in a subtype of estrogen receptor negative breast cancer is controlled by FoxA1

Abstract

Breast cancer is a heterogeneous disease and several distinct subtypes exist based on differential gene expression patterns. Molecular apocrine tumors were recently identified as an additional subgroup, characterised as ERα- AR+, but with an expression profile that resembles ERα+ luminal breast cancer. Previously, we mapped global AR binding events in a cell line model of molecular apocrine breast cancer (termed MDA-MB-453 cells) using ChIP-seq. Our results suggested that these tumours are driven by AR through its interaction with critical ER cis-regulatory elements, resulting in a transcriptional programme reminiscent of ER-mediated transcription in luminal breast cancers. Additionally, we found that AR binding is a near-perfect subset of FoxA1 binding regions, a level of concordance never previously seen with a Nuclear Receptor. By silencing FoxA1 using specific siRNA, we observe dramatic changes in the gene expression profile of the cells (730 genes are differentially expressed) including many of the signature molecular apocrine genes. Furthermore, silencing of FoxA1 in these breast cancer cells results in altered AR binding to the chromatin (lost, conserved and de novo binding events are found) as has been previously seen in the prostate cancer cell line, LNCaP. We are investigating this phenomenon further using proteomics to discover new AR interacting proteins and histone mark ChIP-seq to understand the proteins and epigenetic events that may mediate the reprogrammed AR binding in the absence of FoxA1.