breast-cancer

RUNX1 loss combined with p53 deletion creates aggressive ER+ breast tumors with immune cell infiltration

RUNX1 is a transcription factor that is mutated in a subset of estrogen receptor-positive (ER+) breast cancers, but whether RUNX1 loss actually causes tumors to form has been unclear. Using genetically engineered mice with mammary-specific RUNX1 deletion — alone or combined with deletion of RB1 or p53 — this study systematically tested its tumor-suppressive role.

RUNX1 loss alone, or with RB1 loss, was not sufficient to drive tumor formation. But combined loss of RUNX1 and p53 induced mammary tumors with full penetrance (all animals developed tumors). These tumors were ER+ and showed extensive T cell and macrophage infiltration, making them immune-active — potentially relevant to immunotherapy response.

This establishes RUNX1 as a genuine tumor suppressor in ER+ breast cancer in collaboration with p53, with potential implications for patient stratification.

Key Findings

Combined RUNX1 and p53 loss induces fully penetrant mammary tumor formation
RUNX1 loss alone or with RB1 co-deletion was insufficient for tumorigenesis
Resulting tumors are ER+ and immune-active (T cell and macrophage infiltration)
Immune-active tumor microenvironment suggests potential immunotherapy sensitivity
RUNX1 acts as tumor suppressor in ER+ breast cancer in a p53-dependent context

Implications

ER+ breast cancer patients with RUNX1 mutations may have distinct tumor biology — specifically an immune-active microenvironment — that could predict better responses to immune checkpoint therapy. This challenges the view that ER+ breast cancer is immunologically 'cold' and suggests that molecular subtype beyond ER status matters for immunotherapy selection.

Caveats

Preprint — not peer reviewed. Based on abstract only. Mouse model — human RUNX1-mutant ER+ breast cancers need direct analysis. Immune phenotype in mice may not translate to human tumors. Whether the immune infiltration is antitumor or protumor in this context is not established from the abstract.

Source: bioRxiv — 2026-04-09

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