Expression of the high-affinity fluoropyrimidine-preferring nucleoside transporter hCNT1 correlates with decreased disease-free survival in breast cancer.
OBJECTIVE
Nucleoside and nucleobase derivatives are currently used in the treatment of a variety of solid tumors; however, the role of plasma membrane transporters as biomarkers of drug metabolism has not been fully addressed. Thus, the purpose of this study was to determine whether the concentrative nucleoside transporter hCNT1 is a predictive marker of therapeutic response.


METHODS
We studied a cohort of 90 breast cancer patients who were treated with cyclophosphamide-methotrexate-5-fluorouracil after surgery and then monitored for up to 108 months. hCNT1 and enzymes associated with nucleotide metabolism (thymidine phosphorylase, dihydropyrimidine dehydrogenase and thymidylate synthase) were assessed immunohistochemically in tissue samples.


RESULTS
Human CNT1 presence was mostly cytoplasmic, with some nuclear staining. The percentage of hCNT1-positive cells correlated positively with the expression of thymidine phosphorylase and dihydropyrimidine dehydrogenase. Nuclear staining correlated negatively with decreased disease-free survival, whereas the percentage of hCNT1-positive cells correlated positively with reduced long-term survival, with the hCNT1-positive index (>80%) being indicative of poor prognosis. A relative risk of relapse was associated with high hCNT1-positive indexes, whereas when this parameter was combined with the nodal status (positive), a high risk of relapse was found, suggesting that both parameters may reflect a poor prognosis.


CONCLUSIONS
These results indicate that the expression of the high-affinity concentrative nucleoside transporter hCNT1 has a prognostic value in determining disease-free survival and risk of relapse in breast cancer patients undergoing surgery followed by cyclophosphamide-methotrexate-5-fluorouracil chemotherapy.
Gloeckner-Hofmann
Katharina
K
Institute of Pathology, Klinikum Kassel, Kassel, Germany.
Guillén-Gómez
Elena
E
Schmidtgen
Claudia
C
Porstmann
Romy
R
Ziegler
Ralf
R
Stoss
Oliver
O
Casado
F Javier
FJ
Rüschoff
Josef
J
Pastor-Anglada
Marçal
M
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis
D014408:Biomarkers, Tumor; D026901:Membrane Transport Proteins; C065171:cif nucleoside transporter; D003520:Cyclophosphamide; D005472:Fluorouracil; D008727:Methotrexate