FOXA1 overexpression mediates endocrine resistance by altering the ER transcriptome and IL-8 expression in ER-positive breast cancer

Abstract

Forkhead box protein A1 (FOXA1) is a pioneer factor of estrogen receptor α (ER)-chromatin binding and function, yet its aberration in endocrine-resistant (Endo-R) breast cancer is unknown. Here, we report preclinical evidence for a role of FOXA1 in Endo-R breast cancer as well as evidence for its clinical significance. FOXA1 is gene-amplified and/or overexpressed in Endo-R derivatives of several breast cancer cell line models. Induced FOXA1 triggers oncogenic gene signatures and proteomic profiles highly associated with endocrine resistance. Integrated omics data reveal IL8 as one of the most perturbed genes regulated by FOXA1 and ER transcriptional reprogramming in Endo-R cells. IL-8 knockdown inhibits tamoxifen-resistant cell growth and invasion and partially attenuates the effect of overexpressed FOXA1. Our study highlights a role of FOXA1 via IL-8 signaling as a potential therapeutic target in FOXA1-overexpressing ER-positive tumors. A bout 75% of breast cancers express estrogen receptor α (ER), which is a strong driver and therapeutic target for these ER-positive ( + ) tumors. Endocrine therapy with aromatase inhibitors lowers the level of estrogen; selective ER modulators such as tamoxifen (Tam) bind to and block ER, and down-regulators such as fulvestrant (Ful) bind to ER and induce its degradation. Endocrine therapy prolongs disease-free and overall survival when used in the adjuvant setting and can induce long-term remission in some patients in the metastatic setting. Despite the overall success of endocrine therapy, tumors in more than 50% of patients with metastatic disease fail to respond, and nearly all metastatic patients with initially responding tumors eventually experience tumor relapse and die from acquired resistance (1, 2). Although there are many causes for resistance, the most predominant mechanisms include altered ER signaling and interactions between ER, its coregulators, and various growth factor pathways. These alterations facilitate adaptation from ligand-dependent to ligand-independent ER activation, which is further triggered by cross-talk with growth factor receptor (GFR) signaling pathways (3-6). However, the key mediators of ER transcriptional reprogramming in promoting endocrineresistant (Endo-R) breast cancer remain poorly understood.Recently, a potential role of the forkhead box protein A1 (FOXA1) has been suggested in mediating endocrine resistance in breast cancer (7,8). FOXA1 is termed a "pioneer factor" because it binds to highly compacted or "closed" chromatin via a domain similar to that of linker histones and, through its C-terminal domain, renders these genomic regions more accessible to other transcription factors, such as ER (9), progesterone receptor (PR) (10), and androgen receptor (AR) (11). As such, FOXA1 has a key role in demarcating the tissue-specific binding sites of these nuclear receptors (12). Together with ER, FOXA1 contributes to the pattern of gene transcription that induces luminal cell differentiation (13) and represses the basal phenotype (14). Like E...

Recurrent and functional regulatory mutations in breast cancer

“…Through its role as a pioneer factor for oestrogen receptor, higher levels of FOXA1 protein may increase cellular sensitivity to oestrogen. While FOXA1 expression has been linked with positive clinical outcome 27–29 , high levels of FOXA1 have recently been associated with poor outcome, metastasis, decreased response to fulvestrant, and endocrine resistance 26,30,31 . Identification of FOXA1 alterations in patients undergoing hormone therapy may thus be important for recognizing mechanisms for resistance to therapy and tumour progression.…”

Identification of Potential Therapeutic Targets Among CXC Chemokines in Breast Tumor Microenvironment Using Integrative Bioinformatics Analysis

“…Tumor necrosis factor α (TNFα)-activated mesenchymal stromal cells accelerate breast tumor progression via neutrophil aggregation [39]. Considering hormone receptor criteria, CXCL8 deficiency inhibits hormone-resistant cell growth and invasion, in part attenuating the effect of Forkhead box protein A1 (FOXA1) function in ER+ breast cancer [40]. …”

Coordinate Enhancer Reprogramming by GATA3 and AP1 Promotes Phenotypic Plasticity to Achieve Breast Cancer Endocrine Resistance

“…To study the molecular mechanism of therapy resistance in breast cancer, we used a tamoxifen-resistant (TamR) cell model that was established through long-term culture of ER+ luminal MCF7 parental (MCF7P) cell line in the presence of tamoxifen [21][22][23] . We first validated the resistance of TamR cells to 4-OHT and morphological changes.…”