Thioredoxin-interacting protein is an independent risk stratifier for breast ductal carcinoma in situ

Abstract

Current clinicopathological parameters are useful predictors of breast ductal carcinoma in situ behavior, but they are insufficient to define high-risk patients for disease progression precisely. Thioredoxin-interacting protein (TXNIP) is a key player of oxidative stress. This study aims to evaluate the role of TXNIP as a predictor of ductal carcinoma in situ progression. Tissue microarrays from 776 pure ductal carcinoma in situ and 239 mixed ductal carcinoma in situ and invasive tumors were constructed. All patients were treated at a single institution with a long-term follow-up and TXNIP expression was assessed using immunohistochemistry. TXNIP expression was investigated in terms of associations with clinicopathological and molecular features and patient outcome. Loss/reduced cytoplasmic expression of TXNIP was associated with features of aggressiveness including high nuclear grade (p = 1.6 × 10), presence of comedo necrosis (p = 0.001), and estrogen receptor negative (ER-)/HER2- ductal carcinoma in situ (p = 4.6 × 10). Univariate analysis showed an inverse association between TXNIP expression and outcome in terms of shorter local recurrence-free survival (p = 0.009). Multivariable analyses showed that independent predictors of ductal carcinoma in situ recurrence were low TXNIP expression (p = 0.005, HR = 0.51, and 95% CI: 0.32-0.81), larger ductal carcinoma in situ size, and high nuclear grade. TXNIP functions as a tumor suppressor gene with loss of its expression associated with ductal carcinoma in situ recurrence. TXNIP can be used as a potentially useful marker in prognostic stratification of ductal carcinoma in situ for management decisions.

Prognostic significance of cathepsin V (CTSV/CTSL2) in breast ductal carcinoma in situ

“…This study consisted of a well-annotated cohort of pure DCIS cases (n=776) and cases associated with synchronous IBC (DCIS-mixed) (n=239), diagnosed at Nottingham Breast Institute, UK, between 1990 and 2012, as previously described 23. Clinicopathological and outcome data were collected, and patients were followed up on an ongoing basis where local recurrence-free interval (LRFI) was defined as any event of ipsilateral local recurrence (either DCIS or IBC), after 6 months from the primary treatment.…”

The prognostic significance of lysosomal protective protein (cathepsin A) in breast ductal carcinoma in situ

“…A large DCIS, well‐characterised annotated cohort, including pure DCIS ( n = 776) and DCIS coexist with IBC (DCIS‐mixed) ( n = 239) presented between 1990 and 2012 at Nottingham City Hospital, Nottingham, United Kingdom was used as previously described . To avoid selection bias, the DCIS‐mixed cohort was selected with clinicopathological features comparable to the pure cohort.…”

“…In addition, molecular classes, hypoxia inducible factor 1 alpha (HIF‐1α) expression and tumour infiltrating lymphocytes (TILs) density were available for the cohort . Briefly, the molecular classes were defined based on the immunohistochemistry (IHC) surrogate classification using oestrogen (ER) and progesterone (PR) receptor, the human epidermal growth factor receptor 2 (HER2) and Ki‐67 status.…”

“…Kingdom was used as previously described. 3,26,32 To avoid selection bias, the DCISmixed cohort was selected with clinicopathological features comparable to the pure cohort.…”

“…In addition, molecular classes, hypoxia inducible factor 1 alpha (HIF-1a) expression and tumour infiltrating lymphocytes (TILs) density were available for the cohort. 23,26,32 Briefly, the molecular classes were defined based on the immunohistochemistry (IHC) surrogate classification using oestrogen (ER) and progesterone (PR) receptor, the human epidermal growth factor receptor 2 (HER2) and Ki-67 status. ER and PR were defined as positive if >1% of tumour cells showed nuclear staining, 33 while HER2 positivity was defined when more than 10% of tumour cells showed strong complete membranous staining (score +3), where borderline cases (+2) were checked using the chromogenic in-situ hybridisation technique (CISH) to assess the gene amplification status.…”