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

Elena Oropeza, Sinem Seker, Sabrina Carrel, Aloran Mazumder, Daniel Lozano, Athena Jimenez, Sabrina N. VandenHeuvel, Dillon A. Noltensmeyer, Nindo B. Punturi, Jonathan T. Lei, Bora Lim, Susan E. Waltz, Shreya A. Raghavan, Matthew N. Bainbridge, Svasti Haricharan

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numberadf2860
Pages (from-to)eadf2860
JournalScience advances
Volume9
Issue number26
DOIs
StatePublished - Jun 30 2023

Keywords

  • Humans
  • Female
  • Aged
  • Breast Neoplasms/drug therapy
  • Epidermal Growth Factor
  • Cell Cycle/genetics
  • Cell Division
  • Mutation
  • Receptors, Estrogen

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Molecular portraits of cell cycle checkpoint kinases in cancer evolution, progression, and treatment responsiveness'. Together they form a unique fingerprint.

Cite this