RNA expression of breast cancer resistance protein, lung resistance-related protein, multidrug resistance-associated proteins 1 and 2, and multidrug resistance gene 1 in breast cancer: correlation with chemotherapeutic response.
OBJECTIVE
The aim of this study was to investigate whether expression of particular drug resistance genes in primary operable breast cancer correlates with response to first-line chemotherapy in advanced disease.


METHODS
We determined mRNA levels of BCRP, LRP, MRP1, MRP2, and MDR1 in 59 primary breast tumor specimens of patients who received chemotherapy as first-line systemic treatment after diagnosis of advanced disease. The relative expression levels were measured by quantitative real-time reverse transcription-PCR and subsequently analyzed in relation to the type of response to chemotherapy, the length of progression-free survival (PFS), and post-relapse overall survival.


RESULTS
For each of these drug resistance genes, a large variation in expression level was observed among the tumors of the different patients. When analyzing mRNA expression in relation to overall response, it was found that the median expression level of these five drug resistance genes in the responding tumors, as compared with nonresponding tumors, was markedly lower. Classification of tumors as high versus low with respect to the expression level of these genes showed that the overall response in the MDR1-high subset (17%), as compared with the MDR1-low subset (68%), was significantly lower (P = 0.005). Although similar differences in response rate were found for subsets of tumors stratified by the expression level of the other drug resistance genes, none of the observed differences were statistically significant. However, in the subgroup of patients treated with anthracycline-based chemotherapy (5-fluorouracil, Adriamycin/epirubicin, and cyclophosphamide), a correlation between response and the expression of BCRP and MRP1 (only PFS) was found, whereas such an association was not present in the cyclophosphamide, methotrexate, and 5-fluorouracil-treated group of patients. Furthermore, high expression of LRP as well as MDR1 was found to be significantly associated with a poor PFS (P = 0.04 and P < 0.001, respectively). For lung resistance-related protein, this association was limited to 5-fluorouracil, Adriamycin/epirubicin, and cyclophosphamide. Expression levels of BCRP, MRP1, or MRP2 were not related with the length of PFS. Furthermore, no correlation between the expression level of these drug resistance genes and post-relapse overall survival was found.


CONCLUSIONS
In this pilot study, MDR1 expression in primary breast tumors was inversely related with the efficacy of first-line chemotherapy, and high expression level was a significant predictor of poor prognosis for patients with advanced disease. Apart from MDR1, the expression levels of BCRP, LRP, and MRP1 might have some additional predictive value for clinical outcome.
Burger
Herman
H
Department of Medical Oncology, Erasmus Medical Center Rotterdam (Daniel den Hoed Kliniek/Josephine Nefkens Institute), 3000 DR Rotterdam, The Netherlands. Burger@oncd.azr.nl
Foekens
John A
JA
Look
Maxime P
MP
Meijer-van Gelder
Marion E
ME
Klijn
Jan G M
JG
Wiemer
Erik A C
EA
Stoter
Gerrit
G
Nooter
Kees
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D017931:DNA Primers; D018432:Drug Resistance, Multiple / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis; D026901:Membrane Transport Proteins; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D012008:Recurrence; D012189:Retrospective Studies; D016019:Survival Analysis; D013997:Time Factors; D014158:Transcription, Genetic / Q000235:genetics; D020394:Vault Ribonucleoprotein Particles / Q000235:genetics*; D000099187:Major Vault Protein
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D017931:DNA Primers; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; C421109:multidrug resistance-associated protein 1