Functional Significance of Mutant p53 in Breast Cancer.

摘要

Approximately 40% of breast cancer patients have tumors containing alterations in the p53 tumor suppressor gene; these patients are known to have a poorer prognosis than those lacking p53 mutations. Arg-His (R-H) mutations are frequently observed at amino acid 175 of p53 (equivalent to murine 172) in such tumors. Expression of a mammary-targeted p53 172R-H transgene rarely induces spontaneous tumors in mice, but carcinogen-treated p53 172R-H transgenic mice develop tumors much earlier than controls. Furthermore, expression of this transgene predisposes tumors induced by carcinogen treatment or oncogene coexpression to the development of aneuploidy. The objective of this proposal is to examine the mechanism by which this particular p53 mutant promotes aneuploidy and tumorigenesis. This will be accomplished through both analysis of gene transcription and analysis of the mitotic machinery and cellular apoptosis. Recent in vitro studies indicate that expression of the p53 17 SR-H mutant in mammary epithelial cells may promote mammary tumorigenesis by deregulating centrosome replication and reducing both basal and DNA-damage-induced apoptosis. Transcriptional regulation studies are currently in progress to identify possible novel protein-protein interactions between the mutant and other proteins leading to the up- or down-regulation of genes linked to the promotion of genomic instability and cancer.