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 outcome, 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 positive correlation of FOXM1 and c-Src expression in human breast cancer and show that the expression of FOXM1 target genes predicts poor outcome 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. Mammary epithelial organoids from a doxycycline-inducible transgenic model of breast cancer (MMTV-rtTA/TetO-PyVmT-IRES-CRE) were used to study the effects of c-Src (Src) deletion on early events in tumorigenesis. Transcriptomic analysis (RNA-Seq) was performed on organoid preparations from three independent groups of mice (n=5) per genotype (wild-type and conditional c-Src knockout), with and without doxycycline treatment to induce expression of the transforming oncogene (polyomavirus middle-T antigen) and Cre recombinase.