HS3ST2 modulates breast cancer cell invasiveness via MAP kinase- and Tcf4-dependent regulation of protease and cadherin expression.

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Abstract

Heparan sulfate 3-O-sulfotransferase 2 (HS3ST2), an enzyme mediating 3-Osulfation 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 HS3ST2 reexpression were investigated in vitro using high and low invasive breast cancer cell lines. Compared to controls, highly invasive HS3ST2-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 CEACAM-1, while protease inhibitor and annexin A10 expression were decreased. Low invasive HS3ST2 -expressing MCF-7 cells became even less invasive, with no change in gelatinolytic MMP activity. HS3ST2 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 HS3ST2-expressing MDA-MB-231 cells, which is a possible underlying cause of increased chemosensitivity towards doxorubicin and paclitaxel in these cells. This study provides the first in vitro evidence of the involvement of HS3ST2 in breast cancer cell invasion and chemosensitivity.

Speakers from the University of Münster

Götte, Martin

Department of Gynecology and Obstetrics

Projects the talk is about

DAAD- Al Tawasul - Syndecan-1 and microRNA function in inflammatory breast cancer Duration: 01/01/2015 - 31/12/2015 Funded by: German Academic Exchange Service Type of project: Participation in other joint projects

IRTG 1549 - Molecular and Cellular Glyco-Sciences (MCGS). Understanding Structure/Function Relationships of Carbohydrate/Protein-Interactions (MCGS) Duration: 10/03/2009 - 31/03/2014 | 1st Funding period Funded by: DFG - International Research Training Group Type of project: Main DFG-project hosted at University of Münster

Publications referred to in the talk

HS3ST2 modulates breast cancer cell invasiveness via MAP kinase-and Tcf4 (Tcf7l2)-dependent regulation of protease and cadherin expression Kumar A., Gassar E., Spillmann D., Stock C., Sen Y., Zhang T., Van Kuppevelt T., Hulsewig C., Kozlowski E., Pavao M., Ibrahim S., Poeter M., Rescher U., Kiesel L., Koduru S., Yip G., Gotte M. (2014) In: International Journal of Cancer, 135(11), 2579-2592. doi:10.1002/ijc.28921 Research article (journal) | Peer reviewed | Published