High ASMA⁺ Fibroblasts and Low Cytoplasmic HMGB1⁺ Breast Cancer Cells Predict Poor Prognosis

Abstract

© 2017 The Authors Breast cancer is a major health problem in Thailand as the first-ranked cancer in Thai women. Using the prognostic markers in both cancer cells and tumor stroma are of benefit for providing an accurate prediction of disease progression. We found that high ASMA+ fibroblasts and low HMGB1 in cancer cells are the most reliable predictors of metastatic relapse. Introduction The influence of cancer-associated fibroblasts (CAFs) and high mobility group box 1 (HMGB1) has been recognized in several cancers, although their roles in breast cancer are unclear. The present study aimed to determine the levels and prognostic significance of α-smooth muscle actin-positive (ASMA+) CAFs, plus HMGB1 and receptor for advanced glycation end products (RAGE) in cancer cells. Materials and Methods A total of 127 breast samples, including 96 malignant and 31 benign, were examined for ASMA, HMGB1, and RAGE by immunohistochemistry. The χ2 test and Fisher's exact test were used to test the association of each protein with clinicopathologic parameters. The Kaplan-Meier method or log-rank test and Cox regression were used for survival analysis. Results ASMA+ fibroblast infiltration was significantly increased in the tumor stroma compared with that in benign breast tissue. The levels of cytoplasmic HMGB1 and RAGE were significantly greater in the breast cancer tissue than in the benign breast tissues. High ASMA expression correlated significantly with large tumor size, clinical stage III-IV, and angiolymphatic and perinodal invasion. In contrast, increased cytoplasmic HMGB1 correlated significantly with small tumor size, pT stage, early clinical stage, luminal subtype (but not triple-negative subtype), and estrogen receptor and progesterone receptor expression. The levels of ASMA (hazard ratio, 14.162; P =.010) and tumor cytoplasmic HMGB1 (hazard ratio, 0.221; P =.005) could serve as independent prognostic markers for metastatic relapse in breast cancer patients. The ASMA-high/HMGB1-low profile provided the most reliable prediction of metastatic relapse. Conclusion We present for the first time, to the best of our knowledge, the potential clinical implications of the combined assessment of ASMA+ fibroblasts and cytoplasmic HMGB1 in breast cancer.