Serglycin Is Implicated in the Promotion of Aggressive Phenotype of Breast Cancer Cells

Abstract

Serglycin is a proteoglycan expressed by some malignant cells. It promotes metastasis and protects some tumor cells from complement system attack. In the present study, we show for the first time the in situ expression of serglycin by breast cancer cells by immunohistochemistry in patients’ material. Moreover, we demonstrate high expression and constitutive secretion of serglycin 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 purified from conditioned medium of MDA-MB-231 cells, and represented the major proteoglycan secreted by these cells, having a molecular size of ∼250 kDa and carrying chondroitin sulfate side chains, mainly composed of 4-sulfated (∼87%), 6-sulfated (∼10%) and non-sulfated (∼3%) disaccharides. Purified serglycin inhibited early steps of both the classical and the lectin pathways of complement by binding to C1q and mannose-binding lectin. Stable expression of serglycin in less aggressive MCF-7 breast cancer cells induced their proliferation, anchorage-independent growth, migration and invasion. Interestingly, over-expression of serglycin lacking the glycosaminoglycan attachment sites failed to promote these cellular functions, suggesting that glycanation of serglycin is a pre-requisite for its oncogenic properties. Our findings suggest that serglycin promotes a more aggressive cancer cell phenotype and may protect breast cancer cells from complement attack supporting their survival and expansion.

Insights into the key roles of proteoglycans in breast cancer biology and translational medicine

“…Recently it has been shown that serglycin promotes breast cancer cell anchorage-independent growth, migration and invasion of breast cancer cells and these properties are dependent on the expression and secretion of glycanated serglycin bearing CS chains [33]. …”

“…Serglycin is highly expressed in breast cancer tissues and cell lines [33]. The mRNA levels of serglycin are markedly up-regulated in aggressive breast cancer cells clustered into Basal B subgroup, which exhibit an EMT gene signature and resemble breast cancer stem cells being CD44 high CD24 low [33].…”

“…The mRNA levels of serglycin are markedly up-regulated in aggressive breast cancer cells clustered into Basal B subgroup, which exhibit an EMT gene signature and resemble breast cancer stem cells being CD44 high CD24 low [33]. Basal-like breast cancers are correlated with increased risk of metastatic spread and poor patient prognosis.…”

“…Basal-like breast cancers are correlated with increased risk of metastatic spread and poor patient prognosis. In contrast, serglycin is expressed in low levels in less aggressive subtypes of breast cancer cells [33]. Biochemical characterization of proteoglycans secreted by aggressive MDA-MB-231 breast cancer cells demonstrated that serglycin bearing CS chains is the major secreted proteoglycan and it is abundantly present in the cytoplasm and cell membrane showing both filamentous and granular distribution [33].…”

“…In contrast, serglycin is expressed in low levels in less aggressive subtypes of breast cancer cells [33]. Biochemical characterization of proteoglycans secreted by aggressive MDA-MB-231 breast cancer cells demonstrated that serglycin bearing CS chains is the major secreted proteoglycan and it is abundantly present in the cytoplasm and cell membrane showing both filamentous and granular distribution [33]. Serglycin promotes breast cancer cell anchorage-independent growth, migration and invasion when it is over-expressed in minimally invasive MCF-7 breast cancer cells.…”