HS3ST2 modulates breast cancer cell invasiveness via MAP kinase‐ and Tcf4 (Tcf7l2)‐dependent regulation of protease and cadherin expression. Issue 11 (30th April 2014)

• Record Type: Journal Article
• Authors: Vijaya Kumar, Archana; Salem Gassar, Ezeddin; Spillmann, Dorothe; Stock, Christian; Sen, Yin‐Ping; Zhang, Ting; Van Kuppevelt, Toin H.; Hülsewig, Carolin; Koszlowski, Eliene O.; Pavao, Mauro S.G.; Ibrahim, Sherif A.; Poeter, Michaela; Rescher, Ursula; Kiesel, Ludwig; Koduru, Suresh; Yip, George W.; Götte, Martin
• Is Part Of: International journal of cancer. Volume 135:Issue 11(2014:Dec. 01)
• Page Start: 2579
• Page End: 2592
• Publication Date: 2014-04-30
• Subjects: Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.28921
• Languages: English
• ISSNs: 0020-7136

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Heparan sulfate 3‐<italic>O</italic>‐sulfotransferase 2 (HS3ST2), an enzyme mediating 3‐<italic>O</italic>‐sulfation of heparan sulfate (HS), is silenced by hypermethylation in breast cancer. As HS has an important co‐receptor function for numerous signal transduction pathways, the phenotypical changes due to <italic>HS3ST2</italic> reexpression were investigated <italic>in vitro</italic> using high and low invasive breast cancer cell lines. Compared to controls, highly invasive <italic>HS3ST2</italic>‐expressing MDA‐MB‐231 cells showed enhanced Matrigel invasiveness, transendothelial migration and motility. Affymetrix screening and confirmatory real‐time PCR and Western blotting analysis revealed increased expression of several matrix metalloproteinases, cadherin‐11, E‐cadherin and <italic>CEACAM‐1</italic>, while protease inhibitor and annexin A10 expression were decreased. Low invasive <italic>HS3ST2</italic> ‐expressing MCF‐7 cells became even less invasive, with no change in gelatinolytic MMP activity. <italic>HS3ST2</italic> expression increased HS‐dependent basal and FGF2‐specific signaling through the constitutively active p44/42 MAPK pathway in MDA‐MB‐231 cells. Increased MAPK activation was accompanied by upregulation of ß‐catenin in MDA‐MB‐231, and of the transcription factor Tcf4 in both cell lines. Dysregulation of Tcf4‐regulated ion transporters and increased cytosolic acidification were observed in <italic>HS3ST2</italic>‐expressing MDA‐MB‐231 cells, which is a possible underlying cause of increased chemosensitivity towards doxorubicine and paclitaxel in these cells. This study provides the first <italic>in vitro</italic> evidence of the involvement of <italic>HS3ST2</italic> in breast cancer cell invasion and chemosensitivity.</p> </abstract>