Estrogen receptor α-mediated signaling inhibits type I interferon response to promote breast carcinogenesis

Area of Science:

• Oncology
• Immunology
• Endocrinology

Background:

• Estrogen receptor alpha (ERα) is a key driver in ~70% of breast cancers, but its role in carcinogenesis is not fully understood.
• The type I interferon (IFN) response plays a crucial role in anti-viral immunity and cancer surveillance.

Purpose of the Study:

• To investigate the role of ERα in regulating the type I IFN response in breast cancer.
• To elucidate the mechanisms by which ERα influences IFN-stimulated gene (ISG) transcription.
• To evaluate the therapeutic potential of targeting ERα in combination with type I IFN therapy.

Main Methods:

• In vitro studies using cell lines to assess ERα's effect on IFN-β-induced ISG transcription.
• Mechanistic studies involving histone variant analysis (H2A.Z) and protein-protein interaction assays (STAT2).
• In vivo studies using a xenograft mouse model and analysis of clinical patient data.

Main Results:

• ERα activation by estradiol inhibits IFN-β-induced ISG transcription, while ERα deficiency or fulvestrant treatment enhances it.
• ERα inhibits ISG transcription by inducing H2A.Z and interacting with STAT2, disrupting the ISGF3 complex.
• Fulvestrant combined with IFN-β suppressed ERα+ breast tumor growth in mice.
• Higher ISG levels in ERα+ breast cancer patients correlate with better long-term survival.

Conclusions:

• ERα acts as a negative regulator of the type I IFN response through two distinct mechanisms, thereby promoting breast carcinogenesis.
• Targeting ERα may enhance the efficacy of type I IFN-based therapies for ERα+ breast cancer.
• The interplay between ERα and the IFN response is a critical factor in breast cancer progression and patient outcomes.