Approximately 80% of human breast carcinomas express oestrogen receptor α (ER) and are treated with therapies that block the synthesis or activity of its primary ligand oestradiol. Although oestrogen withdrawal by treatment with aromatase inhibitors (AIs) is currently the most effective form of endocrine therapy in postmenopausal women, up to 50% of patients derive little or no clinical benefit from treatment. Understanding of the precise molecular effects and causes of resistance is limited.
To better characterise the mechanisms of resistance to oestrogen deprivation, we examined gene expression in 104 patients treated with neoadjuvant anastrozole using Illumina whole genome expression arrays1. Surprisingly, analyses revealed that pretreatment expression of an inflammatory signature correlated with poor response. Poor response was also associated with higher levels of lymphocytic infiltration in the tumour, suggesting that infiltrating immune cells may play a role in response to aromatase inhibitors. These observations were also validated in independent cohorts (p<0.001). These findings contrast with chemotherapy-treated breast cancers where high levels of infiltration are associated with a good response.
Expression of chemokines including CCL5, CXCL16, and CCL22 also increased in response to treatment and this was replicated in vitro in an MCF7 cell model of oestrogen deprivation. In addition, a significant increase in the total number of peripheral blood mononuclear cells migrating to oestrogen deprived cells compared to cells with normal levels of E2 (p <0.0001) was observed in a transwell immune cell migration assay. Furthermore, FACS analysis revealed a significant increase in the number of CD4+ cells and a decrease in the number of CD11+ and CD14+ cells migrating to deprived cells (p<0.05). Together, these data suggest that oestrogen deprivation-induced chemokine production induces recruitment of immune cells towards ER+ve breast cancer cells and that this response may contribute to resistance to anti-oestrogen therapy. Targeting this inflammatory response could be a future direction for therapy.