Molecular portraits of cell cycle checkpoint kinases in cancer evolution, progression, and treatment responsiveness.

Autor: Oropeza E; Aging and Cancer Immunology, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.; NCI-designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Seker S; Aging and Cancer Immunology, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.; NCI-designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Carrel S; Aging and Cancer Immunology, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.; NCI-designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Mazumder A; Aging and Cancer Immunology, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.; NCI-designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Lozano D; Aging and Cancer Immunology, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.; NCI-designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Jimenez A; Aging and Cancer Immunology, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.; NCI-designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., VandenHeuvel SN; Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA., Noltensmeyer DA; Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA., Punturi NB; Aging and Cancer Immunology, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.; NCI-designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Lei JT; Lester and Sue Smith Breast Cancer Center, Baylor College of Medicine, Houston, TX, USA., Lim B; Lester and Sue Smith Breast Cancer Center, Baylor College of Medicine, Houston, TX, USA.; Department of Oncology/Medicine, Baylor College of Medicine, Houston, TX, USA., Waltz SE; Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA.; Research Service, Cincinnati Veteran's Affairs Medical Center, 3200 Vine St., Cincinnati, OH, USA., Raghavan SA; Texas A&M University, College Station, TX, USA., Bainbridge MN; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA., Haricharan S; Aging and Cancer Immunology, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.; NCI-designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2023 Jun 30; Vol. 9 (26), pp. eadf2860. Date of Electronic Publication: 2023 Jun 30.
DOI: 10.1126/sciadv.adf2860
Abstrakt: 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..
Databáze: MEDLINE
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