Abstract
Legumain is a proteolytic enzyme that plays a role in the regulation of cell proliferation in invasive breast cancer. Studies evaluating its role in ductal carcinoma in situ (DCIS) are lacking. Here, we aimed to characterize legumain protein expression in DCIS and evaluate its prognostic significance. Legumain was assessed immunohistochemically in a tissue microarray of a well-characterized cohort of DCIS (n = 776 pure DCIS and n = 239 DCIS associated with invasive breast cancer (DCIS-mixed)). Legumain immunoreactivity was scored in tumor cells and surrounding stroma and related to clinicopathological parameters and patient outcome. High legumain expression was observed in 23% of pure DCIS and was associated with features of high-risk DCIS including higher nuclear grade, comedo necrosis, hormone receptor negativity, HER2 positivity, and higher proliferation index. Legumain expression was higher in DCIS associated with invasive breast cancer than in pure DCIS (p < 0.0001). In the DCIS-mixed cohort, the invasive component showed higher legumain expression than the DCIS component (p < 0.0001). Legumain was an independent predictor of shorter local recurrencefree interval for all recurrences (p = 0.0003) and for invasive recurrences (p = 0.002). When incorporated with other risk factors, legumain provided better patient risk stratification. High legumain expression is associated with poor prognosis in DCIS and could be a potential marker to predict DCIS progression to invasive disease.
Highlights
The key strategies for breast ductal carcinoma in situ (DCIS) management are to prevent its progression into invasive disease and to avoid disease recurrence, invasive breast carcinoma which accounts for half of the recurrences
Currently available risk indices such as Van Nuys Prognostic Index and nomograms rely mainly on clinicopathological parameters and to lesser extent on markers related to the tumor cells with little consideration for the surrounding microenvironment [7, 10,11,12]
With the emerging role of tumor microenvironment and the related proteins in the disease behavior [13], identification of more robust genetic signatures incorporating the crosstalk between tumor epithelial cells and surrounding microenvironment might provide a better approach for DCIS risk assessment and better management
Summary
The key strategies for breast ductal carcinoma in situ (DCIS) management are to prevent its progression into invasive disease and to avoid disease recurrence, invasive breast carcinoma which accounts for half of the recurrences. Since the current clinicopathological parameters are inadequate to define DCIS risk precisely, identification of novel prognostic markers is necessary [2, 3]. Currently available risk indices such as Van Nuys Prognostic Index and nomograms rely mainly on clinicopathological parameters and to lesser extent on markers related to the tumor cells with little consideration for the surrounding microenvironment [7, 10,11,12]. With the emerging role of tumor microenvironment and the related proteins in the disease behavior [13], identification of more robust genetic signatures incorporating the crosstalk between tumor epithelial cells and surrounding microenvironment might provide a better approach for DCIS risk assessment and better management
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