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Riboflavin Trafficking in Breast Cancer
Vanessa M. D'Souza, Ph.D.
School of Pharmacy, University of Maryland, Baltimore
Riboflavin (vitamin B2), a water-soluable vitamin, serves as a precursor for the biosynthesis of coenzymes FMN (riboflavin 5-phosphate) and FAD (flavin adenine dinucleotide) that are crucial to oxidation-reduction reactions involved in cellular metabolic pathways. Dietary intake of this essential vitamin contibutes to maintaining nutritional homeostasis in humans, whereas deficiency in vitamin intake could lead to physiological disturbances such as anemia, cardiovascular disease, neurodegenerative disorders, and although not conclusively shown in humans, possibly cancer. Consequently, the mechanism(s) underlying cellular riboflavin uptake has generated considerable interest.
Recently, our laboratory proposed a receptor-mediated endocytic pathway for riboflavin uptake in human adenocarcinoma (Caco-2) and choriocarcinoma (BeWo) cell lines. The model proposes a role for riboflavin binding proteins (RfBP) in sequestering riboflavin followed by internalization via cell surface receptors. BfBP are 37 kDa estrogen-responsive phosphoglycoproteins overexpressed in rapidly dividing cells such as the fetus and breast carcinomas and have a suggested role as serum and tissue markers in clinical screening of breast tumors. The identity of the receptor(s) involved remains elusive. Cubilin (460 kDa) coexpressed with megalin (600 kDa) are multiligand endocytic receptors localized at the apical pole of various epithelia and have been identified in the apical translocation of vitamin binding proteins, apolipoproteins, peptides, hormones, enzymes, and more recently, transferrin. Hence, the current study aims to identify and characterize riboflavin transport via this receptor-mediated system in breast cancer.
Understanding the biology of breast tumors with focus on the vitamin B2 transport system offers a novel platform that may be further exploited within the diagnostic and chemotherapeutic realm of breast cancer. Tumor-specific imaging of localized ligands (e.g., vitamin derivatives), in addition to a role in targeted drug delivery (e.g., riboflavin analogs) are strategies that would contribute to improving the current diagnostic and treatment modalities of breast cancer.
