p53 Mediates Vast Gene Expression Changes That Contribute to Poor Chemotherapeutic Response in a Mouse Model of Breast Cancer12

• Published in: Translational oncology 2018-05, Vol.11 (4), p.930-940
• Main Authors: Tonnessen-Murray, Crystal, Ungerleider, Nathan A., Rao, Sonia G., Wasylishen, Amanda R., Frey, Wesley D., Jackson, James G.
• Format: Article
• Language: English
• Subjects: Original article
• ISSN: 1936-5233
• DOI: 10.1016/j.tranon.2018.05.003

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 ( Trp5 3-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 Trp 53 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 retained arrest capacity (responded poorly) and those that proliferated (responded well) after treatment had remarkably different gene regulation. For instance, Cdkn1a -null tumors that arrested upregulated Cdkn2a (p16), suggesting an alternative, p21-independent route to arrest. Live animal imaging of longitudinal gene expression of a senescence/inflammation gene reporter in Trp53 +/+ tumors showed induction during and after chemotherapy treatment, while tumors were arrested, but expression rapidly diminished immediately upon relapse.