P53 AND P-GLYCOPROTEIN ARE OFTEN COEXPRESSED AND ARE ASSOCIATED WITH POOR-PROGNOSIS IN BREAST-CANCER

Expression of both P-glycoprotein (P-gp) and mutant p53 have recently been reported to be associated with poor prognosis of breast cancer. T he expression of P-gp is associated in vitro and in vivo with cross-re sistance to several anti-cancer drugs. p53 plays a regulatory role in apoptosis, and mutant p53 has been suggested to be involved in drug re sistance. Interestingly, in vitro experiments have shown that mutant p 53 can activate the promoter of the MDR1 gene, which encodes P-gp. We investigated whether p53 and P-gp are simultaneously expressed in prim ary breast cancer cells and analysed the impact of the co-expression o n patients' prognosis. Immunohistochemistry was used to investigate P- gp expression (JSB-1, C219) and nuclear p53 accumulation (DO-7) in 20 operable chemotherapy untreated and 30 locally advanced breast cancers undergoing neoadjuvant chemotherapy with doxorubicin and cyclophospha mide. Double immunostaining showed that P-gp expression and nuclear p5 3 accumulation often occur concomitantly in the same tumour cells. A c orrelation between p53 and P-gp expression was found in all 50 breast cancers (P = 0.003; Fisher's exact test). P-gp expression, nuclear p53 accumulation, and co-expression of p53 and P-gp were more frequently observed in locally advanced breast cancers than in operable breast ca ncers (P = 0.0004; P = 0.048; P = 0.002 respectively, Fisher's exact t est). Go-expression of p53 and P-gp was the strongest prognostic facto r for shorter survival by multivariate analysis (P = 0.004) in the gro up of locally advanced breast cancers (univariate analysis: P = 0.0007 ). Only 3 out of 13 samples sequentially taken before and after chemot herapy displayed a change in P-gp or p53 staining. In conclusion, nucl ear p53 accumulation is often associated with P-gp expression in prima ry breast cancer, and simultaneous expression of p53 and P-gp is assoc iated with shorter survival in locally advanced breast cancer patients . Co-expression of P-gp and mutant p53 belong to a series of molecular events resulting in a more aggressive phenotype, drug resistance and poor prognosis.