P53 and its molecular basis to chemoresistance in breast cancer.
BACKGROUND
TP53 mutations have been associated with resistance to anthracyclines and mitomycin in breast cancer. This review examines the potential roles of different components in the p53 cascade with respect to drug resistance.


METHODS
Literature was searched using the ISI Web and Pubmed. Considering p53 activation in response to genotoxic stress and phosphorylations by ataxia telangiectasia mutated/ataxia telangiectasia and radiation resistance gene 3 related (ATM/ATR). Downstream checkpoint proteins chk1 and chk2 are also considered to be of major importance. Recently, nonsense mutations in CHEK2, encoding the chk2 protein, were found to predict resistance to anthracycline therapy in some tumours harbouring wild-type TP53. While mouse double minute (MDM)2 or MDMX protein overexpression (often due to gene amplifications) may inactivate p53 in different tumour forms, so far, there is no evidence for MDM2 amplifications in breast cancers resistant to anthracyclines. The roles of p53 isoforms and p53-induced transcription of non-coding RNA remain to be defined.


CONCLUSIONS
Disturbances affecting the 'p53 pathway(s)' may play a key role in chemoresistance in cancer. Although TP53 is not a clinical marker for drug resistance, like other genes (such as breast cancer associated 1/2 (BRCA1/2)) it may be considered a 'beacon' identifying critical gene cascades.
Section of Oncology, Institute of Medicine, University of Bergen, 5020 Bergen, Norway.
Stian
S
Knappskog
Per Eystein
PE
Lønning
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D064447:Checkpoint Kinase 2; D019008:Drug Resistance, Neoplasm; D005260:Female; D016158:Genes, p53; D006801:Humans; D051379:Mice; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D016159:Tumor Suppressor Protein p53; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases