Activation of the MDR1 upstream promoter in breast carcinoma as a surrogate for metastatic invasion.
OBJECTIVE
Activation of the MDR1 upstream promoter (USP) has been described previously in four lymphoblastic leukemia patients, where it is the major MDR1 promoter associated with P-glycoprotein overexpression. We asked whether MDR1 USP-derived transcripts were also present in breast carcinoma and assessed their potential as a biomarker.


METHODS
We developed a sensitive method for detecting transcripts derived from the MDR1 USP and used it to identify MDR1 USP-derived transcripts in cell model systems, in 61 breast carcinoma biopsies of the primary tumor, and in isolated malignant epithelial cells both from the primary tumor and from the associated invaded lymph nodes.


RESULTS
The MDR1 USP was not active in several independent leukemic and breast cancer cell lines or nucleated peripheral blood cells (n = 9). However, transcripts derived from the MDR1 USP were detected in some drug-resistant cell lines and a high proportion of primary breast tumors (71.6%; n = 61), whereas they were present at low frequency in normal breast tissue (10%; n = 10). Activation of MDR1 USP was not due to chromosomal amplifications or rearrangements at the MDR1 locus. Transcription from the MDR1 USP correlated with metastatic node invasion [N = 0-3 versus N > 3 (N = number of lymph nodes invaded); Fisher's exact test, P = 0.011] and was detected in malignant epithelial cells from the primary tumor and those that metastasized to the lymph nodes.


CONCLUSIONS
MDR1 USP activation is a surrogate marker for breast carcinoma progression and can be used as a marker to study breast cancer susceptibility.
Raguz
Selina
S
Clinical Sciences Centre, Medical Research Council, Imperial College, Hammersmith Hospital, London, United Kingdom.
Tamburo De Bella
Manuela
M
Tripuraneni
Gopichani
G
Slade
Martin J
MJ
Higgins
Christopher F
CF
Coombes
R Charles
RC
Yagüe
Ernesto
E
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D014408:Biomarkers, Tumor; D015139:Blotting, Southern; D001940:Breast / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D019450:Genes, MDR / Q000235:genetics*; D006801:Humans; D007945:Leukemia, Lymphoid / Q000235:genetics; D008207:Lymphatic Metastasis; D008875:Middle Aged; D008957:Models, Genetic; D009362:Neoplasm Metastasis; D010641:Phenotype; D011401:Promoter Regions, Genetic; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D012313:RNA