dataset
posted on 2023-03-31, 04:22 authored by Anni Laine, Srikar G. Nagelli, Caroline Farrington, Umar Butt, Anna N. Cvrljevic, Julia P. Vainonen, Femke M. Feringa, Tove J. Grönroos, Prson Gautam, Sofia Khan, Harri Sihto, Xi Qiao, Karolina Pavic, Denise C. Connolly, Pauliina Kronqvist, Laura L. Elo, Jochen Maurer, Krister Wennerberg, Rene H. Medema, Heikki Joensuu, Emilia Peuhu, Karin de Visser, Goutham Narla, Jukka Westermarck Supplementary Data from CIP2A Interacts with TopBP1 and Drives Basal-Like Breast Cancer Tumorigenesis
Funding
Academy of Finland (Suomen Akatemia)
Finnish Cancer Foundations
Sigrid Juselius Foundation
National Cancer Institute (NCI)
United States Department of Health and Human Services
Find out more...National Institutes of Health (NIH)
U.S. Department of Defense (DOD)
History
ARTICLE ABSTRACT
Basal-like breast cancers (BLBC) are characterized by defects in homologous recombination (HR), deficient mitotic checkpoint, and high-proliferation activity. Here, we discover CIP2A as a candidate driver of BLBC. CIP2A was essential for DNA damage–induced initiation of mouse BLBC-like mammary tumors and for survival of HR–defective BLBC cells. CIP2A was dispensable for normal mammary gland development and for unperturbed mitosis, but selectively essential for mitotic progression of DNA damaged cells. A direct interaction between CIP2A and a DNA repair scaffold protein TopBP1 was identified, and CIP2A inhibition resulted in enhanced DNA damage–induced TopBP1 and RAD51 recruitment to chromatin in mammary epithelial cells. In addition to its role in tumor initiation, and survival of BRCA-deficient cells, CIP2A also drove proliferative MYC and E2F1 signaling in basal-like triple-negative breast cancer (BL-TNBC) cells. Clinically, high CIP2A expression was associated with poor patient prognosis in BL-TNBCs but not in other breast cancer subtypes. Small-molecule reactivators of PP2A (SMAP) inhibited CIP2A transcription, phenocopied the CIP2A-deficient DNA damage response (DDR), and inhibited growth of patient-derived BLBC xenograft. In summary, these results demonstrate that CIP2A directly interacts with TopBP1 and coordinates DNA damage–induced mitotic checkpoint and proliferation, thereby driving BLBC initiation and progression. SMAPs could serve as a surrogate therapeutic strategy to inhibit the oncogenic activity of CIP2A in BLBCs.
These results identify CIP2A as a nongenetic driver and therapeutic target in basal-like breast cancer that regulates DNA damage–induced G2–M checkpoint and proliferative signaling.
