i(3)so3-galactosylceramide and Carcinogenesis

Basal-like breast cancer (BLBC) is associated with a poor clinical outcome as a result of the few treatment options and poor therapeutic response. Here, we report that elevated expression of urine diphosphate-galactose ceramide galactosyltransferase (UGT8) specifically occurs in BLBC and predicts poor prognosis in breast cancer patients. UGT8 expression is transcriptionally up-regulated by Sox10, triggering the sulfatide biosynthetic pathway; increased sulfatide activates integrin αVβ5-mediated signaling that contributes to BLBC progression. UGT8 expression promotes, whereas UGT8 knockdown suppresses tumorigenicity and metastasis. Importantly, we identify that zoledronic acid (ZA), a marketed drug for treating osteoporosis and bone metastasis, is a direct inhibitor of UGT8, which blocks the sulfatide biosynthetic pathway. Significantly, a clinically achievable dosage of ZA exhibits apparent inhibitory effect on migration, invasion, and lung metastasis of BLBC cells. Together, our study suggests that UGT8 is a potential prognostic indicator and druggable target of BLBC and that pharmacologic inhibition of UGT8 by ZA offers a promising opportunity for treating this challenging disease.

Topics: Animals; Biosynthetic Pathways; Breast Neoplasms; Carcinogenesis; Cell Line, Tumor; Cell Movement; Disease Progression; Female; Ganglioside Galactosyltransferase; Gene Expression Regulation, Neoplastic; Humans; Mice, SCID; Neoplasm Invasiveness; Neoplasm Metastasis; Receptors, Vitronectin; Signal Transduction; SOXE Transcription Factors; Sulfoglycosphingolipids; Survival Analysis; Up-Regulation; Zoledronic Acid