Enhanced IFNα Signaling Promotes Ligand-Independent Activation of ERα to Promote Aromatase Inhibitor Resistance in Breast Cancer

Abstract

Aromatase inhibitors (AIs) reduce estrogen levels up to 98% as the standard practice to treat postmenopausal women with estrogen receptor-positive (ER+) breast cancer. However, approximately 30% of ER+ breast cancers develop resistance to treatment. Enhanced interferon-alpha (IFNα) signaling is upregulated in breast cancers resistant to AIs, which drives expression of a key regulator of survival, interferon-induced transmembrane protein 1 (IFITM1). However, how upregulated IFNα signaling mediates AI resistance is unknown. In this study, we utilized MCF-7:5C cells, a breast cancer cell model of AI resistance, and demonstrate that these cells exhibit enhanced IFNα signaling and ligand-independent activation of the estrogen receptor (ERα). Experiments demonstrated that STAT1, the mediator of intracellular signaling for IFNα, can interact directly with ERα. Notably, inhibition of IFNα signaling significantly reduced ERα protein expression and ER-regulated genes. In addition, loss of ERα suppressed IFITM1 expression, which was associated with cell death. Notably, chromatin immunoprecipitation experiments validated that both ERα and STAT1 associate with ERE sequences in the IFITM1 promoter. Overall, hyperactivation of IFNα signaling enhances ligand-independent activation of ERα, which promotes ER-regulated, and interferon stimulated gene expression to promote survival in AI-resistant breast cancer cells.

Influence of Estrogen Treatment on ESR1+ and ESR1− Cells in ER+ Breast Cancer: Insights from Single-Cell Analysis of Patient-Derived Xenograft Models

“…In some LTED cell lines, growth factor receptors and downstream signaling pathways—including the MAPK, PI3K/AKT/mTOR, and JNK pathways—could function as alternative growth signaling pathways, independent of ER [ 36 ], or via ER–growth factor coregulation mechanisms [ 37 ]. Cell lines and a PDX model have been used to investigate the mechanism of varying responses to E2 in breast cancer [ 20 , 38 , 39 , 40 , 41 , 42 ]. In our investigations of the SC31 and GS3 PDX models by scRNA-Seq, we obtained new and valuable information on how E2 suppresses the growth of patient-derived tumors in the murine PDX model.…”

Action of Estrogen In Breast Cancer: A review Study

“…For example, the transcription factor, nuclear factors NF-kB are phosphorylated following activation of the PI3`K/Akt kinase by E2, and then this NF-kB phosphorylation leads to increased expression of genes that contain NF-kB response elements.The NF-kB may be a target for phosphorylation by AKT kinases (Barreto, Mcgovern and Garcia-segura, 2021). Thus , PI3`K signaling activates AKT and NF-kB signaling, causing cell survival (apoptosis inhibition) (Escher et al, 2021). Furthermore, a high interdependence between PI3`K and ER signaling pathways may be also involved in activation of the estrogen independent-ER pathway via PI3`K/ AKT/ mTOR, resulting in enhanced cellular proliferation in absence of the estrogen.…”