RUNX1-deficiency drives immune-active ER⁺ mammary tumorigenesis through activation of interferon signaling

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Recurrent loss-of-function mutations in RUNX1 are observed in estrogen receptor-positive (ER+) breast cancers.
• The precise role of RUNX1 loss in breast tumorigenesis is not fully understood.

Purpose of the Study:

• To investigate the role of RUNX1 loss in breast cancer initiation using genetically engineered mouse models.
• To elucidate the mechanisms by which RUNX1 deficiency contributes to ER+ breast cancer development.

Main Methods:

• Utilized genetically engineered mouse models with conditional gene disruption in luminal mammary epithelial cells (MECs).
• Assessed tumor formation upon loss of RUNX1 alone, combined with RB1, or combined with p53.
• Analyzed tumor microenvironment, including immune cell infiltration and gene expression profiles.

Main Results:

• Combined loss of RUNX1 and p53 induced ER+ mammary tumors with high penetrance.
• Tumors exhibited extensive T cell and macrophage infiltration, indicating an immune-hot microenvironment.
• RUNX1 deficiency activated interferon signaling and derepressed RUNX1 target STAT1 in luminal MECs, enhancing inflammatory responses.

Conclusions:

• RUNX1 loss, particularly in combination with p53 loss, drives the initiation of an immune-active subtype of ER+ breast cancer.
• Elevated immune signatures and poorer patient survival correlate with low RUNX1 expression in human ER+ breast cancers.
• RUNX1 acts as a tumor suppressor in ER+ breast cancer by regulating inflammatory responses and immune cell infiltration.