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J Exp Med. 2018 Jun 4;215(6):1679-1692. doi: 10.1084/jem.20172048. Epub 2018 May 4.

Inhibition of UGT8 suppresses basal-like breast cancer progression by attenuating sulfatide-αVβ5 axis.

Cao Q1,2, Chen X1,2, Wu X1,2, Liao R1,2, Huang P1,2, Tan Y1,2, Wang L3, Ren G3, Huang J1, Dong C4,2.

Author information

1
Department of Pathology and Pathophysiology and Department of Surgical Oncology (Breast Center), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
2
Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou, China.
3
Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
4
Department of Pathology and Pathophysiology and Department of Surgical Oncology (Breast Center), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China chenfangdong@zju.edu.cn.

Abstract

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.

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