S100A8 gene copy number and protein expression in breast cancer: associations with proliferation, histopathological grade and molecular subtypes

Abstract

Background and aims: Amplification of S100A8 occurs in 10-30% of all breast cancers and has been linked to poorer prognosis. Similarly, the protein S100A8 is overexpressed in a roughly comparable proportion of breast cancers and is also found in infiltrating myeloid-lineage cells, again linked to poorer prognosis. We explore the relationship between these findings.

Methods: We examined S100A8 copy number (CN) alterations using fluorescence in situ hybridization in 475 primary breast cancers and 117 corresponding lymph nodes. In addition, we studied S100A8 protein expression using immunohistochemistry in 498 primary breast cancers from the same cohort.

Results: We found increased S100A8 CN (≥ 4) in tumor epithelial cells in 20% of the tumors, increased S100A8 protein expression in 15%, and ≥ 10 infiltrating S100A8 + polymorphonuclear cells in 19%. Both increased S100A8 CN and protein expression in cancer cells were associated with high Ki67 status, high mitotic count and high histopathological grade. We observed no association between increased S100A8 CN and S100A8 protein expression, and only a weak association (p = 0.09) between increased CN and number of infiltrating S100A8 + immune cells. Only S100A8 protein expression in cancer cells was associated with significantly worse prognosis.

Conclusions: Amplification of S100A8 does not appear to be associated with S100A8 protein expression in breast cancer. S100A8 protein expression in tumor epithelial cells identifies a subgroup of predominantly non-luminal tumors with a high mean age at diagnosis and significantly worse prognosis. Finally, S100A8 alone is not a sufficient marker to identify infiltrating immune cells linked to worse prognosis.

Keywords: Amplification; Breast cancer; Copy number; MDSC; Protein expression; S100A8.

Fig. 1

Overview of the study population. Inclusion and exclusion criteria

Fig. 2

Fluorescence in situ hybridization for S100A8 at 60x magnification, scale bars: 20 μm, showing increased copy number of S100A8 (red dots) in tumor cell nuclei stained with Dapi (blue)

Fig. 3

Immunohistochemical staining showing positive cytoplasmic staining at 400x magnification in (a) cancer cells, and (b) infiltrating polymorphonuclear cells

Fig. 4

Breast cancer specific survival based on proportion of S100A8 + tumor epithelial cells using a log-normal AFT model. Time ratios as well as p-values are given in Table 6