Loss of HSulf-1 expression enhances autocrine signaling mediated by amphiregulin in breast cancer

Keishi Narita, Jeremy Chien, Sally A. Mullany, Julie Staub, Xiang Qian, Wilma L. Lingle, Viji Shridhar

Research output: Contribution to journalArticlepeer-review

64 Scopus citations


Heparan sulfate (HS) glycosaminoglycans are the oligosaccharide chains of heparan sulfate proteoglycans. The sulfation of HS glycosaminoglycan residues is required for its interaction with various heparin-binding growth factors to promote their biological activities to activate their high affinity receptor tyrosine kinases.Wehave identifiedHSglycosaminoglycan-6-O-endosulfatase HSulf-1 as a down-regulated gene in ovarian, breast, and several other cancer cell lines. Here we have shown that HSulf-1 inhibits autocrine activation of the EGFR-ERK (epidermal growth factor receptor-extracellular signal-regulated kinase) pathway induced by serum withdrawal in MDA-MB-468 breast cancer cells. Short hairpin RNA-mediated down-regulation of HSulf-1 in HSulf-1 clonal lines of MDA-MB-468 led to a significant increase in autocrine activation of ERK compared with vector only control. The autocrine signaling was also inhibited with neutralization antibodies against amphiregulin and HB-EGF, the heparin-binding growth factor family of the EGF superfamily. Furthermore, HSulf-1-mediated inhibition of autocrine signaling was associated with reduced cyclin D1 levels, leading to decreased S phase fraction and increased G 2-M fraction, as well as increased cell death. Finally, evaluation of HSulf-1 expression levels in primary invasive breast tumors by RNA in situ hybridization indicated that HSulf-1 is down-regulated in the majority (60%) of tumors, with a predominant association with lobular histology. These data suggest a potential role of HSulf-1 down-regulation in mammary carcinogenesis.

Original languageEnglish (US)
Pages (from-to)14413-14420
Number of pages8
JournalJournal of Biological Chemistry
Issue number19
StatePublished - May 11 2007

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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