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J. Biol. Chem., Vol. 282, Issue 19, 14413-14420, May 11, 2007

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Loss of HSulf-1 Expression Enhances Autocrine Signaling Mediated by Amphiregulin in Breast Cancer^*

From the Department of Laboratory Medicine and Experimental Pathology, Mayo Clinic Cancer Center, Rochester, Minnesota 55905

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. We have identified HS glycosaminoglycan-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 G₂–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.

Received for publication, December 12, 2006 , and in revised form, March 14, 2007.

^* This work was supported by grants from the NCI, National Institutes of Health (CA106954-03), the John W. Anderson Foundation, the Mayo Clinic Bernard and Edith Waterman Center for Cancer Genetics, and the Mayo Foundation (all to V. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Mayo Clinic College of Medicine, 200 First St., S.W., Rochester, MN 55905. Tel.: 507-266-2775; Fax: 507-266-5193; E-mail: shridhar.vijayalakshmi{at}mayo.edu.

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