FOXA1 overexpression mediates endocrine resistance by increasing IL-8 in oestrogen receptor-positive breast cancer

Endocrine resistance is a major obstacle in treating patients with oestrogen receptor (ER)-positive (+) breast cancer. To better understand the mechanism of endocrine resistance, we developed preclinical endocrine-resistant (Endo-R) cell line models and characterized these models at multi-OMICS levels using next-generation sequencing that includes genome-wide Exome-seq and RNA-seq, and ChIP-seq focusing on a pioneer factor of ER-chromatin binding and function, FOXA1. We found that FOXA1 was gene amplified and overexpressed in two independently developed MCF7 tamoxifen-resistant (TamR) derivatives (MCF7L-TamR, MCF7RN-TamR). Induced FOXA1 overexpression triggers an oncogenic gene signature highly associated with the gene signatures of TamR cells in vitro and xenograft tumours in vivo, and leads to endocrine resistance. A FOXA1 copy number gain- associated gene signature predicts poor outcome in patients with ER tumours. Integrated OMICS data reveals interleukin (IL)-8 as one of the most perturbed genes under FOXA1 and ER regulation in TamR cells. Our data also suggest that high levels of FOXA1 may coordinate in ER transcriptional reprogramming towards a more growth factor induced- cistromic profile. IL-8 knockdown inhibits TamR cell growth and invasion, and partially attenuates the effect of overexpressed FOXA1 in ER breast cancer cells. Our study highlights a novel stoichiometric role of FOXA1 via IL-8 signaling as a potential therapeutic target in FOXA1-overexpressing ER tumours.