2. Academic Validation
  3. Reciprocal feedback regulation of ST3GAL1 and GFRA1 signaling in breast cancer cells

Reciprocal feedback regulation of ST3GAL1 and GFRA1 signaling in breast cancer cells

  • Cancer Lett. 2018 Oct 10;434:184-195. doi: 10.1016/j.canlet.2018.07.026.
Tan-Chi Fan 1,  Hui Ling Yeo 2,  Huan-Ming Hsu 3,  Jyh-Cherng Yu 4,  Ming-Yi Ho 1,  Wen-Der Lin 5,  Nai-Chuan Chang 1,  John Yu 1,  Alice L Yu 6
Affiliations

Affiliations

  • 1 Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
  • 2 Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan; Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan.
  • 3 Department of Surgery, Tri-Service General Hospital Songshan Branch, National Defense Medical Center, Taipei, Taiwan; Division of General Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
  • 4 Division of General Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
  • 5 Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Department of Biochemistry and Molecular Biology, Chang Gung University, Gueishan, Taoyuan, Taiwan.
  • 6 Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Genomics Research Center, Academia Sinica, Taipei, Taiwan; Department of Pediatrics/Hematology Oncology, University of California in San Diego, San Diego, CA, USA. Electronic address: a1yu@ucsd.edu.
PMID: 30040982 DOI: 10.1016/j.canlet.2018.07.026
Abstract

GFRA1 and RET are overexpressed in Estrogen Receptor (ER)-positive breast cancers. Binding of GDNF to GFRA1 triggers RET signaling leading to ER phosphorylation and estrogen-independent transcriptional activation of ER-dependent genes. Both GFRA1 and RET are membrane proteins which are N-glycosylated but no O-linked sialylation site on GFRA1 or RET has been reported. We found GFRA1 to be a substrate of ST3GAL1-mediated O-linked sialylation, which is crucial to GDNF-induced signaling in ER-positive breast Cancer cells. Silencing ST3GAL1 in breast Cancer cells reduced GDNF-induced phosphorylation of RET, Akt and ERα, as well as GDNF-mediated cell proliferation. Moreover, GDNF induced transcription of ST3GAL1, revealing a positive feedback loop regulating ST3GAL1 and GDNF/GFRA1/RET signaling in breast cancers. Finally, we demonstrated ST3GAL1 knockdown augments anti-cancer efficacy of inhibitors of RET and/or ER. Moreover, high expression of ST3GAL1 was associated with poor clinical outcome in patients with late stage breast Cancer and high expression of both ST3GAL1 and GFRA1 adversely impacted outcome in those with high grade tumors.

Keywords

GFRA1; Glycosylation; RET; Sialyltransferase.

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