Additive effect of the AZGP1, PIP, S100A8 and UBE2C molecular biomarkers improves outcome prediction in breast carcinoma

Abstract

The deregulation of key cellular pathways is fundamental for the survival and expansion of neoplastic cells, which in turn can have a detrimental effect on patient outcome. To develop effective individualized cancer therapies, we need to have a better understanding of which cellular pathways are perturbed in a genetically defined subgroup of patients. Here, we validate the prognostic value of a 13-marker signature in independent gene expression microarray datasets (n = 1,141) and immunohistochemistry with full-faced FFPE samples (n = 71). The predictive performance of individual markers and panels containing multiple markers was assessed using Cox regression analysis. In the external gene expression dataset, six of the 13 genes (AZGP1, NME5, S100A8, SCUBE2, STC2 and UBE2C) retained their prognostic potential and were significantly associated with disease-free survival (p < 0.001). Protein analyses refined the signature to a four-marker panel [AZGP1, Prolactin-inducible protein (PIP), S100A8 and UBE2C] significantly correlated with cycling, high grade tumors and lower disease-specific survival rates. AZGP1 and PIP were found in significantly lower levels in invasive breast tissue as compared with adjacent normal tissue, whereas elevated levels of S100A8 and UBE2C were observed. A predictive model containing the four-marker panel in conjunction with established clinical variables outperformed a model containing the clinical variables alone. Our findings suggest that deregulated AZGP1, PIP, S100A8 and UBE2C are critical for the aggressive breast cancer phenotype, which may be useful as novel therapeutic targets for drug development to complement established clinical variables.

Zinc-α2-Glycoprotein Exerts Antifibrotic Effects in Kidney and Heart

“…A growing number of clinical studies suggesting that AZGP1 plays a role in many different cancers [20][21][22] implies that our data might be relevant to the field of oncology. If it is correct that AZGP1 exerts antitumor effects through inhibition of TGFb, 24 AZGP1-deficient mice would be expected to have a higher susceptibility for tumor progression.…”

“…26 Enhanced tumor progression has been shown to correlate with lower expression of epithelial AZGP1. [20][21][22][23] Kong et al 24 found that AZGP1 expression can preserve epithelial integrity by promoting mesenchymal-toepithelial transition in pancreatic cancer cells. Kong et al 24 attributed the prodifferentiation effects of AZGP1 to TGF-b antagonistic properties.…”

“…19 Interestingly, AZGP1 has been shown to promote epithelial cell differentiation and stabilization during carcinogenesis. [20][21][22][23] Along these lines, AZGP1 was linked to inhibition of TGFb-mediated dedifferentiation in pancreatic cancer cells. 24 On the basis of these data, we tested the hypothesis that AZGP1 negatively regulates the development of organ fibrosis.…”

Protein S100-A8: A potential metastasis-associated protein for breast cancer determined via iTRAQ quantitative proteomic and clinicopathological analysis

“…The results demonstrated that protein S100-A8 expression levels were significantly associated with the histological type (P= 0.022) and ER positive expression (P=0.009) of breast cancer tumors. Concordantly, Parris et al (33) proposed a combined predictive model for breast cancer outcomes, containing a four-marker panel (α-2-glycoprotein 1, zinc-binding, prolactin-inducible protein, S100-A8 and ubiquitin conjugating enzyme E2 C), which suggested a significant correlation with histological grade, tumor inflammatory cell infiltration, ER and PR status.…”

“…However, protein S100-A8 was also demonstrated to be a marker of poor prognosis for invasive ductal carcinoma of the breast (35). The aforementioned four-marker panel proposed by Parris et al (33) may be used to predict an unfavorable clinical outcome of patients with breast cancer. The present study implemented the Cox proportional hazards model, which demonstrated that protein S100-A8 is not an independent risk factor for prognosis in breast cancer.…”