MDR1 and thymidylate synthase (TS) gene expressions in advanced breast cancer: relationships to drug exposure, p53 mutations, and clinical outcome of the patients.
To characterize the biological features of advanced breast cancer associated with poor chemotherapy response and worse prognosis, sequential tumor samples obtained from 75 patients receiving primary chemotherapy were analysed for MDR1 and TS gene expression before and after treatment. MDR1 gene expression was also analysed in 36 sequential normal samples. The levels of MDR1 and TS genes expression were determined by reverse transcription-PCR method, and examined in relation to p53 gene status, and the clinical outcome of the patients. After treatment, MDR1 expression levels were significantly enhanced in tumor (p = 0.0033) and normal (p = 0.0098) samples, whereas a significant decrease in TS expression was observed (p = 0.0054). There was no significant correlation between MDR1 or TS expressions and the presence of p53 mutations (detected in 24% of the cases), chemoresponsiveness, or survival. Only p53 mutations were associated with reduced disease-free survival (p = 0.0473). These results demonstrate that MDR1 and TS gene expressions were affected by drug exposure, but not by p53 gene status. Furthermore, the 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 tumoral clones, which can be responsible for the absence of relationship of MDR1 expression with clinical outcome of advanced breast cancer patients.
Lizard-Nacol
S
S
Centre Georges François Leclerc, Dijon, France. Slizard@dijon.fnclcc.fr
Genne
P
P
Coudert
B
B
Riedinger
J M
JM
Arnal
M
M
Sancy
C
C
Brunet-Lecomte
P
P
Fargeot
P
P
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015870:Gene Expression / Q000187:drug effects; D016158:Genes, p53; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013940:Thymidylate Synthase / Q000096:biosynthesis*; D016896:Treatment Outcome
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004317:Doxorubicin; D003520:Cyclophosphamide; D013940:Thymidylate Synthase; D005472:Fluorouracil