p53 and P-glycoprotein are often co-expressed and are associated with poor prognosis in breast cancer

Abstract

Summary Expression of both P-glycoprotein (P-gp) and mutant p53 have recently been reported to be associated with poor prognosis of breast cancer. The expression of P-gp is associated in vitro and in vivo with cross-resistance to several anti-cancer drugs. p53 plays a regulatory role in apoptosis, and mutant p53 has been suggested to be involved in drug resistance. Interestingly, in vitro experiments have shown that mutant p53 can activate the promoter of the MDRI gene, which encodes P-gp. We investigated whether p53 and P-gp are simultaneously expressed in primary breast cancer cells and analysed the impact of the co-expression on 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 cyclophosphamide. Double immunostaining showed that P-gp expression and nuclear p53 accumulation often occur concomitantly in the same tumour cells. A correlation 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 cancers (P=0.0004; P=0.048; P=0.002 respectively, Fisher's exact test). Co-expression of p53 and P-gp was the strongest prognostic factor for shorter survival by multivariate analysis (P=0.004) in the group of locally advanced breast cancers (univariate analysis: P=0.0007). Only 3 out of 13 samples sequentially taken before and after chemotherapy displayed a change in P-gp or p53 staining. In conclusion, nuclear p53 accumulation is often associated with Pgp expression in primary breast cancer, and simultaneous expression of p53 and P-gp is associated 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.

Prognostic role of clinical, pathological and biological characteristics in patients with locally advanced breast cancer

“…Riou et al (1993) studied the prognostic significance of nuclear accumulation of p53 in 24 patients with inflammatory breast cancer, and they observed a worse prognosis for patients with nuclear accumulation of p53. Earlier we have reported that co-expression of P-gp and p53 were indicative of a worse prognosis in LABC patients (Linn et al, 1996), and this remained so in this slightly larger group of patients. Expression of one of these factors did not have prognostic significance.…”

Coexpression of p53 protein and MDR functional phenotype in leukemias: The predominant association in chronic myeloid leukemia

“…Pgp and MRP have recently been showed to be activated in association with overexpression of mutant or inactivated p53 protein (11). Coexpression of p53 protein and efflux pumps occurs in solid tumors, representing the strongest prognostic factor for shorter survival in locally advanced breast cancer (49), and is associated with a poor prognosis in osteosarcoma (50). Few reports have shown this association in malignant hematological diseases (10,36,37) and, in this study, no significant association between p53 expression and MDR functional phenotypes was observed in ALL, CLL, and AML.…”

Tacrolimus, a Calcineurin Inhibitor, Overcomes Treatment Unresponsiveness Mediated by P-glycoprotein on Lymphocytes in Refractory Rheumatoid Arthritis

“…Drug resistance is partly caused by disturbance of the drug exclusion pump of P-glycoprotein on the surface of tumor cells [4][5][6][7][8] . P-glycoprotein is induced by transcription factor YB-1, which is activated by various external stimuli such as drugs and inflammatory cytokines and is expressed on cells following the induction of multidrug resistance gene (MDR-1).…”