Different mutant/wild-type p53 combinations cause a spectrum of increased invasive potential in nonmalignant immortalized human mammary epithelial cells.
Aberrations of p53 occur in most, if not all, human cancers. In breast cancer, p53 mutation is the most common genetic defect related to a single gene. Immortalized human mammary epithelial cells resemble the earliest forms of aberrant breast tissue growth but do not express many malignancy-associated phenotypes. We created a model of human mammary epithelial tumorigenesis by infecting hTERT-HME1 immortalized human mammary epithelial cells expressing wild-type p53 with four different mutant p53 constructs to determine the role of p53 mutation on the evolution of tumor phenotypes. We demonstrate that different mutant/wild-type p53 heterozygous models generate loss of function, dominant negative activity, and a spectrum of gain of function activities that induce varying degrees of invasive potential. We suggest that this model can be used to elucidate changes that occur in early stages of human mammary epithelial tumorigenesis. These changes may constitute novel biomarkers or reveal novel treatment modalities that could inhibit progression from primary to metastatic breast disease.
Junk
Damian J
DJ
Cancer Biology Graduate Interdisciplinary Program, The University of Arizona, Tucson, AZ 85724, USA.
Vrba
Lukas
L
Watts
George S
GS
Oshiro
Marc M
MM
Martinez
Jesse D
JD
Futscher
Bernard W
BW
D000256:Adenoviridae / Q000235:genetics; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D005434:Flow Cytometry; D005799:Genes, Dominant; D006801:Humans; D047468:Immunoprecipitation; D009154:Mutation / Q000235:genetics*; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013347:Subcellular Fractions; D019098:Telomerase / Q000378:metabolism; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D004247:DNA; D019098:Telomerase