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It is believed that breast cancer stem cells (BCSCs), like normal stem cell counterparts, have the capacity of self-renewal and differentiation. Simultaneously, estrogen receptor (ER)-negative (-) BCSCs are affected by surrounding differentiated ER-positive (+) tumor cells by virtue of paracrine signaling within the tumor micro-environment. Genistein (GEN), as a sort of phytoestrogen, can act on ER+ breast cancer cells but the role of GEN in the differentiation of neighboring ER- BCSCs has not been defined. Transwell co-culture system was utilized so as to elaborate the interaction between well-differentiated ER+ breast cancer cells (MCF-7) and ER- breast cancer stem/progenitor cells (mammospheres derived from MDA-MB-231 cells). GEN-induced differentiation of BCSCs was analyzed by mammospheres formation assay, flow cytometry and RT-PCR after a 3 day solo-culture or co-culture. We find that GEN sized 2 µM, and 40 nM, effectively promotes morphological alteration of mammospheres, reduces the ratio of subset of CD44+/CD24-/ESA+ cells and upregulates the expression of differentiated cell markers of mammospheres in co-culture system, but not in solo-culture condition. Besides, we demonstrate that the differentiation-inducing effect of GEN on mammospheres is associated with PI3K/Akt and MEK/ERK signaling pathways which are activated by amphiregulin released from ER+ cancer cells. These results indicate that GEN was able to induce the differentiation of breast cancer stem/progenitor cells through interaction with ER+ cancer cells by a paracrine mechanism.

The aim of this study was to establish a prognostic risk model for patients with triple negative breast cancer (TNBC). A total of 278 specimens of human TNBC tissues were investigated by immunohistochemistry for growth-arrest specific protein 6 expression, infiltrations of stromal natural killer cells and tumor-associated macrophages. According to their prognostic risk scores based on the model, patients were divided into three groups (score 0, 1-2, 3). Correlations of prognostic risk scores, clinicopathologic features and overall survival (OS) were analyzed. To study the clinical value of this stratification model in early disease recurrence or metastasis, 177 patients were screened out for further analysis. Based on disease free survival (DFS), 90 patients fell within the DFS ≤3 years group and 87 patients within the DFS ≥5 years group. We analyzed the differences in prognostic risk scores between the two groups. The prognostic risk scores were negatively related to tumor size, lymph node metastasis and P53 status (P < 0.001 for all). Patients with low prognostic risk scores had longer OS (P = 0.001). Using multivariate analysis, it was determined that TNM stage (HR = 0.432, 95% confidence interval [CI] = 0.281-0.665, P = 0.003), FOXP3 positive lymphocytes (HR = 1.712, 95% CI = 1.085-2.702, P = 0.021) and prognostic risk scores (HR = 1.340, 95% CI = 1.192-1.644, P = 0.005) were independent prognostic factors for OS. Compared with the DFS ≥5 years group, the DFS ≤3 years group patients had significantly higher prognostic risk scores (P < 0.001). In conclusion, the prognostic risk score of the model was a significant indicator of prognosis for patients with TNBC.

Early detection and treatment of human colorectal cancers remain a challenge. Identification of new potential markers may help in the diagnosis of colorectal cancer. By comparative two-dimensional gel electrophoresis using extracts from colorectal tumor and adjacent normal tissues, we identified a calcium-binding protein, S100A11, which was highly expressed in colorectal cancer compared with adjacent normal tissues. We expanded our study in 89 clinical colorectal tumor samples to validate this finding and correlates S100A11 expression in human colorectal cancer tissues with various stages of the tumor by Western blotting and immunohistochemical staining. We identified a calcium-binding protein, S100A11, which was highly expressed in colorectal cancer compared with adjacent normal tissues. S100A protein was expressed predominantly in the cytoplasm of normal tissue; however, it was expressed in both the nuclei and cytoplasm of colorectal cancer. S100A11 level in colorectal cancer tissue was increased following stage progression of the disease. These findings suggest S100A11 could be helpful in the pathological study of colorectal cancer, especially for the classification of different stages in colorectal cancer.

The nuclear factor of the activated T cell (NFAT) family was primarily recognized for its central role in T lymphocyte activation. Recent evidence showed that NFAT isoforms participate in the regulation of genes related to cell proliferation and differentiation in epithelial malignancies. Here, we investigated the expression and activation of the calcineurin/NFAT transcription pathway and its role in hepatocellular carcinoma (HCC) proliferation. Expression of NFATc1 and calcineurin proteins was examined by immunohistochemical analyses in 76 human HCC samples. The cellular NFAT activation and distribution in HepG2 cells were analyzed by immunofluorescence and western blot analyses. After NFATc1 expression was knocked down by NFATc1-specific siRNA, we analyzed its implications in cell cycle progression and growth by MTT and flow cytometry. The impact of calcineurin/NFAT signaling on protein expression of c-myc and cox-2 were performed by western blot analyses. NFATc1 is significantly overexpressed in HCC. The regulation of calcineurin activity by ionomycin or cyclosporin A caused rapid nuclear import or export of NFATc1 in HepG2 cells. NFATc1 knock-down led to a significant reduction in proliferation rates and cell cycle arrest at G1 phase. The expression of c-myc and cox-2 was decreased in the NFATc1 knock-down HepG2 cells. Ionomycin increased c-myc and cox-2 expression in HepG2 cells, but not in siNFATc1 HepG2 cells. The calcineurin/NFATc1 signal is overexpressed and active in HCC. It may enhance the proliferative potential of HepG2 cells through transcriptional activation of the c-myc and cox-2 oncogenes.