Reference Number: 130028
Principal Investigator: Dr. Achilleas Theocharis
Organization: Laboratory of Biochemistry
Department of Chemistry, University of Patras, Greece
Period: Grant 2013 April 2013 - March 2015
Grant Title: Biological roles of serglycin in breast cancer
Abstract
Proteoglycans control numerous normal and pathological processes. During tumor development
and growth, proteoglycan expression is markedly modified in the tumor microenvironment.
Altered expression of proteoglycans in cancer cells affects cancer cell signaling, growth andsurvival, cell adhesion, migration and angiogenesis. Although serglycin has been initiallycharacterized as intracellular proteoglycan present mainly in hematopoietic cells, recent data
indicate that it is expressed by cancer cells and may be important for cancer cell biology. The
biological role of serglycin in cancer remains unknown, therefore the aim of the present study was
to investigate the expression and biological role of serglycin in breast cancer. We examined theeffect of serglycin on breast cancer cell properties and phenotype. We also investigated the abilityof serglycin to regulate complement system activity and osteoclastogenesis.
We showed the in situ expression of serglycin by breast cancer cells by immunohistochemistry inpatients' material. Moreover, we demonstrated high expression and constitutive secretion ofserglycin in the aggressive MDA-MB-231 breast cancer cell line. Serglycin exhibited a strong
cytoplasmic staining in these cells, observable at the cell periphery in a thread of filaments near
the cell membrane, but also in filopodia-like structures. Serglycin was associated withintracellular proteins involved in cytoskeleton formation and mRNA maturation and translation.
Serglycin was purified from conditioned medium of MDA-MB-231 cells, and represented themajor proteoglycan secreted by these cells, Serglycin carried chondroitin sulfate side chains,mainly composed of 4-sulfated disaccharides. Stable expression of serglycin in less aggressive
MCF-7 breast cancer cells induced their proliferation, anchorage-independent growth, migrationand invasion through activation of chemokine signaling pathways. Interestingly, over-expressionof serglycin lacking the glycosaminoglycan attachment sites failed to promote these cellularfunctions, suggesting that glycanation of serglycin is a pre-requisite for its oncogenic properties.
Serglycin over-expression in breast cancer cells induced the biosynthesis of inflammatory
mediators such as interleukins and their receptors as well as matrix degrading enzymes. Purified
serglycin inhibited early steps of both the classical and the lectin pathways of complement bybinding to C1q and mannose-binding lectin. Furthermore, serglycin strongly bound toosteoprotegerin. Serglycin promoted osteoclastogenesis and biosynthesis of bone degrading
enzymes since it bound to osteoprotegerin and reduced its ability to block the action of RANKL
in relation to differentiation of osteoclasts.
Our findings suggest that serglycin promotes a more aggressive breast cancer cell phenotype andaugments breast cancer-induced bone destruction. Furthermore, it may also protect breast cancer
cells from complement system attack supporting their survival and expansion.