Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients.
BACKGROUND
The persistence of circulating tumor cells (CTC) in breast cancer patients might be associated with stem cell like tumor cells which have been suggested to be the active source of metastatic spread in primary tumors. Furthermore, these cells also may undergo phenotypic changes, known as epithelial-mesenchymal transition (EMT), which allows them to travel to the site of metastasis formation without getting affected by conventional treatment. Here we evaluated 226 blood samples of 39 metastatic breast cancer patients during a follow-up of palliative chemo-, antibody - or hormonal therapy for the expression of the stem cell marker ALDH1 and markers for EMT and correlated these findings with the presence of CTC and response to therapy.


METHODS
2 x 5 ml blood was analyzed for CTC with the AdnaTest BreastCancer (AdnaGen AG) for the detection of EpCAM, MUC-1 and HER2 transcripts. The recovered c-DNA was additionally multiplex tested for three EMT markers [Twist1, Akt2, PI3Kalpha] and separately for the tumor stem-cell markers ALDH1. The identification of EMT markers was considered positive if at least one marker was detected in the sample.


RESULTS
97% of 30 healthy donor samples investigated were negative for EMT and 95% for ALDH1 transcripts. CTC were detected in 69/226 (31%) cancer samples. In the CTC (+) group, 62% were positive for at least one of the EMT markers and 69% for ALDH1, respectively. In the CTC (-) group the percentages were 7% and 14%, respectively. In non-responders, EMT and ALDH1 expression was found in 62% and 44% of patients, in responders the rates were 10% and 5%, respectively.


CONCLUSIONS
Our data indicate that a major proportion of CTC of metastatic breast cancer patients shows EMT and tumor stem cell characteristics. Further studies are needed to prove whether these markers might serve as an indicator for therapy resistant tumor cell populations and, therefore, an inferior prognosis.
Aktas
Bahriye
B
Department of Gynecology and Obstetrics, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany. bahriye.aktas@uk-essen.de
Tewes
Mitra
M
Fehm
Tanja
T
Hauch
Siegfried
S
Kimmig
Rainer
R
Kasimir-Bauer
Sabine
S
D000328:Adult; D000368:Aged; D000444:Aldehyde Dehydrogenase / Q000032:analysis; D000080924:Aldehyde Dehydrogenase 1 Family; D018952:Antigens, CD34 / Q000032:analysis; D000943:Antigens, Differentiation / Q000032:analysis*; D015415:Biomarkers; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000097:blood* / Q000737:chemistry / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000097:blood / Q000737:chemistry / Q000473:pathology / Q000556:secondary*; D045744:Cell Line, Tumor / Q000737:chemistry; D054338:Cell Transdifferentiation; D004847:Epithelial Cells / Q000737:chemistry* / Q000473:pathology; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000032:analysis; D008648:Mesoderm / Q000737:chemistry* / Q000473:pathology; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis*; D009360:Neoplastic Cells, Circulating / Q000737:chemistry*; D014411:Neoplastic Stem Cells / Q000737:chemistry*; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000473:pathology; D050697:Retinal Dehydrogenase; D055815:Young Adult
D018952:Antigens, CD34; D000943:Antigens, Differentiation; D015415:Biomarkers; D014408:Biomarkers, Tumor; D007527:Isoenzymes; D009363:Neoplasm Proteins; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase