Coordinated activation of c-Src and FOXM1 drives tumor cell proliferation and breast cancer progression

Activation of the tyrosine kinase c-Src promotes Breast Cancer progression and poor outcomes, yet the underlying mechanisms are incompletely understood. Here, we show that deleting c-Src abrogates the activity of Forkhead Box M1 (FOXM1), a master transcriptional regulator of the cell cycle, in a genetically engineered model mimicking the Luminal B molecular subtype of Breast Cancer. By phosphorylating it on two tyrosine residues, c-Src stimulates the nuclear localization of FOXM1 and the expression of its target genes, including key regulators of G2-M cell cycle progression as well as c-Src itself. This positive feedback loop drives proliferation in genetically engineered and patient-derived models of Luminal B-like Breast Cancer. Targeting this mechanism, including through novel compounds that destabilize the FOXM1 protein, induces G2-M cell cycle arrest and Apoptosis, blocking tumor progression and impairing metastasis. We identify a positive correlation between FOXM1 and c-Src expression in human Breast Cancer and show that the expression of FOXM1 target genes predicts poor outcomes and associates with the Luminal B subtype, which responds poorly to approved therapies. These findings indicate that a regulatory network centered on c-Src and FOXM1 is a targetable vulnerability in aggressive luminal breast cancers.