Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK.
EMBO J. 2011 Jun 24;30(15):3019-27. 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.
乳腺癌是一种异质性疾病，根据不同的基因表达模式存在几种不同的亚型。最近发现，分子大汗腺癌是另一个亚组，其特点是雌激素受体阴性和雄激素受体阳性（ER-AR+），但表达谱类似于 ER+腔面乳腺癌。对于这种明显的不一致，一种可能的解释是 AR 可以重现 ER 基因表达程序。我们使用 ER-AR+分子大汗腺癌的细胞系模型（称为 MDA-MB-453 细胞），绘制了全球 AR 结合事件图谱，发现了与乳腺癌细胞中 ER 结合相似的结合图谱。我们发现 AR 结合是 FoxA1 结合区域的一个近乎完美的子集，这种一致性程度以前从未在核受体中见过。AR 的功能依赖于 FoxA1，因为沉默 FoxA1 会抑制 AR 结合、大多数分子大汗腺基因特征的表达和细胞生长。这些发现表明，AR 在分子大汗腺癌中结合并调节 ER 顺式调控元件，导致转录程序类似于腔面乳腺癌中 ER 介导的转录。
