Background p53 mutation influences breast cancer cell growth and patient prognosis. However, different p53 mutations impart specific functions to the mutant protein, including dominant negative or gain of function effects. Mutant p53 molecules R273H and R175H are commonly found in primary breast cancers and are present in the MDA-MB-468 and SKBR3 cell lines, respectively. To compare the direct effects of these two mutations in vivo in an identical cellular background, H1299 (p53-null) cells were constructed to express R273H or R175H p53 mutants. Methods

Thirty female SCID mice were injected subcutaneously with 106 H1299 (p53-null), H1299/R273H or H1299/R175H cells in DMEM + Matrigel (50:50) suspension. Some mice were treated with an Hsp90 inhibitor, which is required for correct folding of many oncogenic proteins. Results

Xenografts bearing R175H showed a mean lag phase (time between cell injection and tumors at exponential growth) of 21 days and a doubling time of 5 days, whereas tumors bearing H1299 (p53-null) or R273H mutation had a lag phase of 31 days with a doubling time of 7 days. Immunohistochemical examination demonstrated a highly heterogeneous pattern of p53 protein expression in the more aggressive R175H expressing cells compared with R273H expressing cells. Hsp90 inhibitor treatment reduced the growth of H1299 and R273H cells, but not R175H cells. Conclusions

The specific p53 mutations directly influence the rate of tumor growth and the p53 protein staining pattern on immunohistochemistry. The differential effects of specific p53 mutations should be considered when interpreting clinical data involving p53 mutation such as in the EORTC 10994 trial, with implications for prognostic determination of individual breast cancer patients.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-03-07.

2010