Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 215, Issue 6, Pages 1679-1692Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20172048
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Funding
- Natural Science Foundation of China [81772801, 81472455]
- Key Program of Zhejiang Province Natural Science Foundation [LZ17H160002]
- National Key R&D Program of China [2016YFC1303200]
- Fundamental Research Funds for Central Universities of China
- Thousand Young Talents Plan of China
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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 alpha V beta 5-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.
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