Breast cancer is a highly heterogeneous disease with a multitude of molecular pathways that interact in the tumor microenvironment in different ways. Signaling networks may diverge to activate several molecular targets or converge towards a single target, interact in antagonistic or cooperative ways, and create positive or negative feedback loops. These interactions are tightly controlled under normal physiological conditions, but this can be disturbed in multiple ways in breast cancer, and the outcome is hard to predict. Recent research has noticeably improved the biological and molecular knowledge regarding breast cancer initiation and progression, identified new biomarkers, and enabled the introduction of new therapeutics. Molecular profiling and a wide range of “omics” studies somewhat overwhelm the current literature, and have not yet fully realized their promise. For example, therapy resistance in breast cancer is a substantial hurdle to treatment, but the mechanisms of resistance remain to be fully defined.

Hormone dependence or independence conditioned by the presence of estrogen receptors (ERs) in breast tumor tissue is still a major factor influencing prognosis and treatment options. Hormone therapy improves patient survival in hormone-dependent breast cancer (i.e. ER+), although there remain a subset of patients who do not respond to the treatment. Hormones (via ERs) and cytokines act as major immunomodulatory molecules in the body and are involved in a variety of physiological processes. They are connected in multi-level combinations forming complex regulatory networks. For example, although there is no direct connection between ERs and interferons (IFNs) as they act in separate biological pathways, they converge indirectly through involvement of other signaling molecules such as nuclear factor kappa B (NFκB), Janus kinase/signal transducers and activators of transcription (JAK-STAT), toll-like receptor (TLR) pathways, cGAS/STING, and mitogen-activated protein kinase (MAPK) [1]. These signaling molecules are also in current focus as they play a significant role in determining the prognosis of breast cancer patients and the development of hormone resistance. In recent years, NFκB has emerged as a particularly promising actor in response to ER and IFN signaling, as it is known to affect nearly every aspect of tumor biology, including promoting cell survival, inducing cell proliferation, promoting metastasis, and stimulating angiogenesis [2], [3].

This review aims to provide a comprehensive analysis of the potential impact of IFNs in hormone-dependent/independent breast cancer, as well as the interaction and cross-talk between IFN and ER signaling. Despite their identification many years ago, this interaction has been largely overlooked in breast cancer research. Additionally, it emphasizes the crucial role of intermediate signaling molecules, and in particular NFκB, due to its substantial association with both ERs and IFNs in breast cancer. Through comprehensive insight into their interactions within the tumor microenvironment, it aims to provide a renewed perspective that could help to better understand breast cancer progression.