MDR1 and thymidylate synthase (TS) gene expressions in advanced breast cancer: Relationships to drug exposure, p53 mutations, and clinical outcome ofthe patients

To characterize the biological features of advanced breast cancer associate d with poor chemotherapy response and worse prognosis, sequential tumor sam ples obtained from 75 patients receiving primary chemotherapy were analysed for MDR1 and TS gene expression before and after treatment. MDR1 gene expr ession was also analysed in 36 sequential normal samples. The levels of MDR 1 and TS genes expression were determined by reverse trnascription-PCR meth od and examined ill relation to p53 gene status, and the clinical outcome o f the patients. After treatment, MDR1 expression levels were significantly enhanced in tumor (p = 0.0033) and normal (p = 0.0098) samples, whereas a s ignificant decrease in TS expression was observed (p = 0.0054). There was n o significant con-elation between MDR1 or TS expressions and the presence o f p53 mutations (detected in 24% of the cases), chemoresponseviness, or sur vival. Only p53 mutations were associated with reduced disease-free surviva l (p = 0.0473). These results demonstrate that MDR1 and TS gene expressions were affected by drug exposure, but not by p53 gene status. Furthermore, t he increase of MDR1 gene expression in normal and tumor tissues is in favor of an induced MDR1 expression rather than of a selection of resistant tumo ral clones, which can be responsible for the absence of relationship of MDR 1 expression with clinical outcome of advanced breast cancer patients.