Abstract P3-10-02: Cell cycle dysregulation in breast cancer: why the details matter

Abstract Cell cycle dysregulation is a prerequisite for cancer formation. However, whether the type of cell cycle dysregulation event a cell incurs during transformation to malignancy influences the type of cancer that evolves or clinical outcome is unknown. In a comprehensive analysis of cell cycle dysregulation in breast cancer patient tumors, we associate mutations in each of four cell cycle checkpoint kinase genes, ATM, CHEK2, ATR and CHEK1, with known tumor characteristics and clinical outcome, and test these associations experimentally using transgenic mice, patient-derived xenografts and breast cancer cell line model systems. Results of this work demonstrate that dysregulation of specific cell cycle checkpoint kinases differently impacts the type of breast cancer that evolves in patients and in experimental model systems, and influences treatment responsiveness and disease progression. For instance, CHEK2 mutations associate preferentially with the incidence of metastatic, premenopausal estrogen receptor (ER)+/HER2- breast cancer in patient data (p=0.001) that is resistant to standard frontline therapy (HR=6.15, p=0.01). These associations appear causal when tested in an immune-competent genetically-engineered mouse model of Chk2 loss, in patient-derived xenograft, and in cell line experiments. On the other hand, ATR mutation by itself is not frequent in ER+/HER2- breast cancer, but co-incident mutation of ATR and TP53 is 2-fold enriched (p=0.002) and associates with metastatic progression (HR=2.01, p=0.007). Concordantly, ATR dysregulation induces metastatic phenotypes in ER+/HER- TP53 mutant, but not in TP53 wildtype, cell lines. Together, these results systematize the impact of individual cell cycle checkpoint kinases on the evolution of cancer subtypes, and on disease progression. Statement of Significance These findings reframe the paradigm of breast cancer classification through the lens of early cell cycle dysregulation events by demonstrating that cell cycle decisions during malignant transformation can direct the type of breast cancer that evolves, how it will respond to treatment, and whether it will metastasize. This work provides rationale for streamlined testing of checkpoint kinase dysregulation to improve precision diagnostics for cancer patients. Citation Format: Sinem Seker, Elena Oropeza, Sabrina Carrel, Aloran Mazumder, Nindo Punturi, Jonathan Lei, Meenakshi Anurag, Bora Lim, Matthew Bainbridge, Svasti Haricharan. Cell cycle dysregulation in breast cancer: why the details matter [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-10-02.