p53 Mediates Vast Gene Expression Changes That Contribute to Poor Chemotherapeutic Response in a Mouse Model of Breast Cancer

Translational Oncology
Crystal Tonnessen-MurrayJames G Jackson

Abstract

p53 is a transcription factor that regulates expression of genes involved in cell cycle arrest, senescence, and apoptosis. TP53 harbors mutations that inactivate its transcriptional activity in roughly 30% of breast cancers, and these tumors are much more likely to undergo a pathological complete response to chemotherapy. Thus, the gene expression program activated by wild-type p53 contributes to a poor response. We used an in vivo genetic model system to comprehensively define the p53- and p21-dependent genes and pathways modulated in tumors following doxorubicin treatment. We identified genes differentially expressed in spontaneous mammary tumors harvested from treated MMTV-Wnt1 mice that respond poorly (Trp53+/+) or favorably (Trp53-null) and those that lack the critical senescence/arrest p53 target gene Cdkn1a. Trp53 wild-type tumors differentially expressed nearly 10-fold more genes than Trp53-null tumors after treatment. Pathway analyses showed that genes involved in cell cycle, senescence, and inflammation were enriched in treated Trp53 wild-type tumors; however, no genes/pathways were identified that adequately explain the superior cell death/tumor regression observed in Trp53-null tumors. Cdkn1a-null tumors that retain...Continue Reading

Citations

Sep 19, 2019·The Journal of Cell Biology·Crystal A Tonnessen-MurrayJames G Jackson
Jan 30, 2020·Molecular & Cellular Oncology·Crystal A Tonnessen-Murray, James G Jackson
Oct 5, 2018·Breast Cancer Research : BCR·Nathan A UngerleiderJames G Jackson
Aug 15, 2019·Proceedings of the National Academy of Sciences of the United States of America·Vinod PantGuillermina Lozano
Feb 18, 2020·Trends in Cancer·Ashkan ShahbandiJames G Jackson

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Methods Mentioned

BETA
RNA-seq
immunoprecipitation
transfection

Software Mentioned

CIBERSORT
IPA
Integrative Genomics Viewer
STAR RNA - seq aligner
GSEA
RSEM
PANTHER
REACTOME GSEA
EBSeq
REACTOME

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