TY - JOUR
T1 - Molecular portraits of cell cycle checkpoint kinases in cancer evolution, progression, and treatment responsiveness
AU - Oropeza, Elena
AU - Seker, Sinem
AU - Carrel, Sabrina
AU - Mazumder, Aloran
AU - Lozano, Daniel
AU - Jimenez, Athena
AU - VandenHeuvel, Sabrina N.
AU - Noltensmeyer, Dillon A.
AU - Punturi, Nindo B.
AU - Lei, Jonathan T.
AU - Lim, Bora
AU - Waltz, Susan E.
AU - Raghavan, Shreya A.
AU - Bainbridge, Matthew N.
AU - Haricharan, Svasti
N1 - Publisher Copyright:
© 2023 The Authors.
PY - 2023/6
Y1 - 2023/6
N2 - 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.
AB - 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.
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U2 - 10.1126/sciadv.adf2860
DO - 10.1126/sciadv.adf2860
M3 - Article
C2 - 37390209
AN - SCOPUS:85164232560
SN - 2375-2548
VL - 9
JO - Science Advances
JF - Science Advances
IS - 26
M1 - adf2860
ER -