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

• Published in: The Journal of clinical investigation Vol. 133; no. 7; pp. 1 - 19
• Main Authors: Nandi, Ipshita, Smith, Harvey W., Sanguin-Gendreau, Virginie, Ji, Linjia, Pacis, Alain, Papavasiliou, Vasilios, Zuo, Dongmei, Nam, Stella, Attalla, Sherif S., Kim, Sung Hoon, Lusson, Sierra, Kuasne, Hellen, Fortier, Anne-Marie, Savage, Paul, Martinez Ramirez, Constanza, Park, Morag, Katzenellenbogen, John A., Katzenellenbogen, Benita S., Muller, William J.
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.04.2023
• Subjects: Ablation; Analysis; Antigens; Apoptosis; Biomedical research; Breast cancer; Breast Neoplasms - pathology; Cell cycle; Cell Cycle - genetics; Cell division; Cell Line, Tumor; Cell Proliferation; Cyclin-dependent kinases; Development and progression; Diagnosis; Female; Forkhead Box Protein M1 - genetics; Forkhead Box Protein M1 - metabolism; Forkhead protein; Forkhead Transcription Factors - metabolism; Gene expression; Gene Expression Regulation, Neoplastic; Genetic engineering; Genetically modified organisms; Humans; Kinases; Localization; Metastases; Metastasis; Oncology; Phosphorylation; Protein-tyrosine kinase; Proteins; Src protein; Tetracycline; Tetracyclines; Therapeutics; Tumors; Tyrosine; Canada; Illinois; Quebec; Oncology; Breast cancer; Mouse models; Cell cycle; Therapeutics
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI162324

Activation of the tyrosine kinase c-Src promotes breast cancer progression and poor outcomes, yet the underlying mechanisms are incompletely understood. Here, we have shown that deletion of c-Src in a genetically engineered model mimicking the luminal B molecular subtype of breast cancer abrogated the activity of forkhead box M1 (FOXM1), a master transcriptional regulator of the cell cycle. We determined that c-Src phosphorylated FOXM1 on 2 tyrosine residues to stimulate its nuclear localization and target gene expression. These included key regulators of G2/M cell-cycle progression as well as c-Src itself, forming a positive feedback loop that drove proliferation in genetically engineered and patient-derived models of luminal B-like breast cancer. Using genetic approaches and small molecules that destabilize the FOXM1 protein, we found that targeting this mechanism induced G2/M cell-cycle arrest and apoptosis, blocked tumor progression, and impaired metastasis. We identified 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 currently approved therapies. These findings revealed a regulatory network centered on c-Src and FOXM1 that is a targetable vulnerability in aggressive luminal breast cancers.