Molecular portraits of cell cycle checkpoint kinases in cancer evolution, progression, and treatment responsiveness
Menée à l'aide de lignées cellulaires, de modèles murins et de données mutationnelles portant sur des patientes atteintes d'un cancer métastatique du sein, cette étude identifie les caractéristiques moléculaires des kinases du contrôle du cycle cellulaire durant l'évolution de la tumeur, sa progression et sa réaction aux traitements
Cell cycle dysregulation is prerequisite for cancer formation. However, it is unknown whether the mode of dysregulation affects disease characteristics. Here, we conduct comprehensive analyses of cell cycle checkpoint dysregulation using patient data and experimental investigations. We find that ATM mutation predisposes the diagnosis of primary estrogen receptor (ER)+/human epidermal growth factor (HER)2− cancer in older women. Conversely, CHK2 dysregulation induces formation of metastatic, premenopausal ER+/HER2− breast cancer (P = 0.001) that is treatment-resistant (HR = 6.15, P = 0.01). Lastly, while mutations in ATR alone are rare, ATR/TP53 co-mutation is 12-fold enriched over expected in ER+/HER2− disease (P = 0.002) and associates with metastatic progression (HR = 2.01, P = 0.006). Concordantly, ATR dysregulation induces metastatic phenotypes in TP53 mutant, not wild-type, cells. Overall, we identify mode of cell cycle dysregulation as a distinct event that determines subtype, metastatic potential, and treatment responsiveness, providing rationale for reconsidering diagnostic classification through the lens of the mode of cell cycle dysregulation.. While all cells must dysregulate the cell cycle to transform into cancer, it turns out that it really matters how they do it..
Science Advances , article en libre accès, 2022