The role of oestrogen receptor-α crosstalk with other steroid receptors in breast cancer

Breast cancer is the most frequently diagnosed cancer in women worldwide. Oestrogen Receptor-α (ERα), is expressed in two thirds of human breast cancers, and the majority of patients are sensitive to endocrine therapy, i.e. anti-oestrogens or aromatase inhibitors that aim to block oestrogen signalling. In addition to ERα, the other members of the steroid receptor family (androgen, AR; progesterone, PR; glucocorticoid, GR; mineralocorticoid receptors, MR) also appear to play an important role in tumour development and recurrence, but the role of this signalling in cancer progression has not been fully characterised. Therefore, this study aims to address the role of the steroid receptor (SR) family members in breast cancer and to assess the effect of receptor crosstalk and downstream signalling. Investigation of receptor signalling crosstalk using reporter, gene expression, proliferation and migration assays, demonstrated that ERα and the other steroid receptors inhibit each other’s activity in endocrine responsive breast cancer cell lines, MCF7 and T47D. Furthermore, treatment with antioestrogen reversed the suppressive effects of ERα on the activity of the other SRs. To characterise receptor crosstalk on a global scale, RNA-seq and ChIP-seq datasets were analysed. Analysis of ChIP-seq data demonstrated that the PR, GR and AR reprogramming of oestrogen signalling results in the loss of ERα canonical binding sites and the gain of novel response elements/binding sites. Motif enrichment analysis of the novel ERα binding sites suggested that the altered binding, in response to AR, GR and PR signalling activation, promotes the recruitment of ERα to androgen, glucocorticoid and progesterone regulatory regions, respectively. Further studies are required to validate these preliminary results to understand the role of steroid receptor crosstalk in breast cancer formation, progression and survival.