title: Matrix detachment and proteasomal inhibitors diminish Sulf-2 expression in breast cancer cell lines and mouse xenografts.
abstract: Sulfatase 2 (Sulf-2) has been previously shown to be upregulated in breast cancer. Sulf-2 removes sulfate moieties on heparan sulfate proteoglycans which in turn modulate heparin binding growth factor signaling. Here we report that matrix detachment resulted in decreased Sulf-2 expression in breast cancer cells and increased cleavage of poly ADP-ribose polymerase. Silencing of Sulf-2 promotes matrix detachment induced cell death in MCF10DCIS cells. In an attempt to identify Sulf-2 specific inhibitor, we found that proteasomal inhibitors such as MG132, Lactacystin and Bortezomib treatment abolished Sulf-2 expression in multiple breast cancer cell lines. Additionally, we show that Bortezomib treatment of MCF10DCIS cell xenografts in mouse mammary fat pads significantly reduced tumor size, caused massive apoptosis and more importantly reduced Sulf-2 levels in vivo. Finally, our immunohistochemistry analysis of Sulf-2 expression in cohort of patient derived breast tumors indicates that Sulf-2 is significantly upregulated in autologous metastatic lesions compared to primary tumors (p < 0.037, Pearson correlation, Chi-Square analysis). In all, our data suggest that Sulf-2 might play an important role in breast cancer progression from ductal carcinoma in situ into an invasive ductal carcinoma potentially by resisting cell death.
authors: Department of Experimental Pathology, Mayo Clinic College of Medicine, 200 First Street, S.W., 2-46 Stabile, Rochester, MN 55905, USA.
authors: Ashwani
authors: A
authors: Khurana
authors: Deok
authors: D
authors: Jung-Beom
authors: Xiaoping
authors: X
authors: He
authors: Sung-Hoon
authors: SH
authors: Kim
authors: Robert C
authors: RC
authors: Busby
authors: Laura
authors: L
authors: Lorenzon
authors: Massimo
authors: M
authors: Villa
authors: Alfonso
authors: A
authors: Baldi
authors: Julian
authors: J
authors: Molina
authors: Matthew P
authors: MP
authors: Goetz
authors: Viji
authors: V
authors: Shridhar
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D018275:Carcinoma, Lobular / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D049109:Cell Proliferation; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D060787:Neoplasm Grading; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013429:Sulfatases; D015238:Sulfotransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D061988:Proteasome Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D015238:Sulfotransferases; C470792:SULF2 protein, human; D013429:Sulfatases