Breast and ovarian cancers: a survey and possible roles for the cell surface heparan sulfate proteoglycans

Abstract

Tumor markers are widely used in pathology not only for diagnostic purposes but also to assess the prognosis and to predict the treatment of the tumor. Because tumor marker levels may change over time, it is important to get a better understanding of the molecular changes during tumor progression. Occurrence of breast and ovarian cancer is high in older women. Common known risk factors of developing these cancers in addition to age are not having children or having children at a later age, the use of hormone replacement therapy, and mutations in certain genes. In addition, women with a history of breast cancer may also develop ovarian cancer. Here, the authors review the different tumor markers of breast and ovarian carcinoma and discuss the expression, mutations, and possible roles of cell surface heparan sulfate proteoglycans during tumorigenesis of these carcinomas. The focus is on two groups of proteoglycans, the transmembrane syndecans and the lipid-anchored glypicans. Both families of proteoglycans have been implicated in cellular responses to growth factors and morphogens, including many now associated with tumor progression.

Figure 1.

Heparan sulfate (HS) biosynthesis. HS synthesis involves sequential addition of N-acetylglucosamine and glucuronic acid (GlcA) residues to a tetrasaccharide linker region, which is covalently linked to the serine residue within the core protein GAG attachment site. Each sugar residue is depicted by a geometric symbol defined in the legend at the top left corner of the figure. The chain then undergoes stepwise modifications beginning with N-deacetylation and N-sulfation of some glucosamine residues. Adjacent to this first modification, some GlcA residues are epimerized to iduronic acid by a 5′ epimerase. Iduronate may then be 2-O-sulfated, with further sulfation on 6-O and 3-O positions on glucosamine residues. None of these modifications goes to completion, leading to a domain structure of HS chains with regions that are highly sulfated, flanked by regions of intermediate sulfation and low sulfation. Much more extensive chain modification is seen in the synthesis of the skeletal polysaccharide, heparin.

Figure 2.

Diagram of syndecans and glypicans. Schematic representations of human syndecan 1–4 monomers (A) and human glypican 1–6 (B) are shown.

Figure 3.

Ovarian carcinoma immunostained for syndecan-1. Serous papillary carcinomas of the ovary, grade II (A) and grade III (B), were stained with mouse monoclonal antibodies against human syndecan-1. (A) The grade II tumor cells strongly express syndecan-1, as shown by the positive cytoplasm. Focal membranous staining is also visible (arrow). Note syndecan-1-positive endothelial cells in the blood vessels (double arrowheads) and positive infiltrating immunological cells in the tumor stroma (arrowhead). (B) Tumor cells of grade III ovarian serous carcinoma show overall strong cytoplasmic and focally nuclear staining for syndecan-1. Scale bar: 100 µm.

Figure 4.

Immunohistochemical staining of human breast tissues for syndecan-1 and syndecan-4. Tissue microarray containing cores of normal human breast (A and B; presented case is AR++, ER+, PR++, and Her2++), intraductal carcinoma (C and D; presented case is AR–, ER+++, PR–, and Her2+++), and invasive ductal carcinoma grade II (E and F; presented case is AR–, ER+, PR–, and Her2+++) and grade III (G and H; presented case is AR–, ER–, PR–, and Her2–) were stained with mouse monoclonal antibodies against human syndecan-1 and syndecan-4. (A) Normal human breast ducts show positive syndecan-1 staining in myoepithelial (arrowhead) and secretory cells (arrow). The positive staining is cytoplasmic as well as nuclear. Endothelial cells of the blood vessels as well as the stromal fibroblasts are also positive (double arrowheads). (B) Syndecan-4 staining shows a predominant nuclear staining pattern (arrow); in addition, the stromal fibroblasts and endothelial cells are also positive (double arrowheads). (C, D) Intraductal carcinoma of the breast has strong cytoplasmic expression of syndecan-1 (C), whereas the syndecan-4 staining is nuclear (D). (E) Invasive ductal carcinoma grade II tumor cells show cytoplasmic expression for syndecan-1 (arrowhead). (F) The tumor cells only show very weak nuclear staining for syndecan-4 (arrowhead); the normal ducts are strongly positive (arrow). (G) Invasive ductal carcinoma grade III shows positive syndecan-1 staining in the cytoplasm (arrowhead). (H) Syndecan-4 shows a nuclear staining pattern (arrowhead). Scale bar: 100 µm (A, B, E–H); 50 µm (C, D).