Overexpression of PBK/TOPK relates to poor prognosis of patients with breast cancer: a retrospective analysis.

BACKGROUND: PDZ-binding kinase/T-lymphokine-activated killer cell-derived protein kinase (PBK/TOPK) is a potential prognostic indicator for patients with breast cancer. The objective of the present study was to explore the relationship between PBK/TOPK expression and clinicopathological indicators as well as the survival of patients with breast cancer. METHODS: Immunohistochemical staining was used to detect the expression of PBK/TOPK in 202 cases of breast cancer tissues. The relationship between PBK/TOPK and clinicopathological parameters was evaluated using Spearman's rank-order correlation. The difference in PBK/TOPK expression among different molecular types was analyzed with the chi-square test. Kaplan-Meier analysis was used to create a survival curve and the log rank test was used to analyze the overall survival (OS) and disease-free survival (DFS). Prognostic correlation was assessed using univariate and multivariate Cox regression analyses. RESULTS: Among 202 breast cancer samples, PBK/TOPK was expressed ("+" and "++") in 182 samples (90.1%). In addition, the histological grade, TNM stages, lymph node metastasis, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), and Ki-67 were positively associated with PBK/TOPK expression. With regard to the molecular type, the expression of PBK/TOPK is different. The expression level of PBK/TOPK was negatively correlated with both the OS and DFS of breast cancer patients. The difference in the above results is meaningful (P < 0.05). CONCLUSIONS: PBK/TOPK is overexpressed in breast cancer, and the expression is closely related to the clinicopathological characteristics of the disease. Breast cancer patients with high expression of PBK/TOPK have a poor prognosis. Therefore, healthcare providers can optimize breast cancer management using this indicator.

The m6A methyltransferase METTL3 promotes the stemness and malignant progression of breast cancer by mediating m6A modification on SOX2.

PURPOSE: We aimed to uncover the role of METTL3 in stimulating the stemness and progression of breast cancer (BCa) through mediating N6-methyladenosine (m6A) modification on SOX2 mRNA. METHODS: METTL3 levels in 48 paired BCa and adjacent normal ones were examined. Kaplan-Meier method was introduced for assessing the prognostic value of METTL3 in BCa. Regulatory effects of METTL3 on invasive and migratory abilities in MCF-7 cells were evaluated by Transwell assay. Besides, the protein levels of SOX2 and tumor stem cell markers CD133 and CD44 in MCF-7 cells affected by METTL3 were determined by Western blot. In addition, the potential interaction between METTL3 and SOX2 was ascertained through RIP (RNA-Binding Protein Immunoprecipitation) assay. Moreover, the interaction between IGF2BP2 and SOX2 influenced by METTL3 was verified by RIP assay as well. RESULTS: METTL3 was upregulated in BCa tissues, especially in T3-T4 or those accompanied with lymphatic metastasis. BCa patients expressing a high level of METTL3 suffered worse prognosis. Knockdown of METTL3 downregulated protein levels of SOX2, CD133 and CD44 in MCF-7 cells. Moreover, invasive and migratory abilities were attenuated in BCa cells with METTL3 knockdown. Silencing of IGF2BP2 markedly downregulated SOX2. RIP assay confirmed the binding between METTL3 and SOX2 mRNA, and knockdown of METTL3 decreased the enrichment of SOX2 in anti-IGF2BP2. Interestingly, overexpression of SOX2 partially reversed the regulatory effects of downregulated METTL3 on MCF-7 cells. CONCLUSIONS: METTL3 is upregulated in BCa, and it promotes the stemness and malignant progression of BCa through mediating m6A modification on SOX2 mRNA.

Clinical Significance of C-X-C Motif Chemokine Receptor 4 and Integrin αvß6 Expression in Breast Cancer.

PURPOSE: C-X-C motif chemokine receptor 4 (CXCR4) and integrin αvß6 play important roles in the malignant progression of multiple cancers. However, it remains unclear whether the expression of one or both proteins in breast cancer (BC) is of clinical significance. In this study, we investigated the expression of CXCR4 and integrin αvß6 in BC tissues and their correlation with clinicopathological characteristics, including survival. METHODS: CXCR4 and αvß6 expression in 111 BC tissues was examined by immunocytochemistry. Correlations between the expression of the 2 proteins and patient clinicopathological characteristic were investigated using the Kaplan-Meier method and the Cox proportional hazards model. RESULTS: CXCR4 and αvß6 were overexpressed in BC tissue compared with normal breast tissue. Overexpression of both molecules was related to lymph node status (p = 0.013 and p = 0.022, respectively). αvß6 overexpression was also associated with tumor size (p = 0.044). A positive correlation was detected between the expression of CXCR4 and αvß6 (r = 0.649, p = 0.001), and co-overexpression of both molecules was associated with tumor size (p = 0.018) and lymph node metastasis (p = 0.015). Kaplan-Meier analysis revealed that overexpression of CXCR4, αvß6, or both molecules was associated with short overall survival (OS; p < 0.001, p < 0.001, and p = 0.009, respectively) and disease-free survival (DFS; p < 0.001, p = 0.005, and p = 0.019, respectively). Multivariate analysis indicated that lymph node metastasis was an independent prognostic factor for unfavorable OS and DFS (p = 0.002 and p = 0.005, respectively), whereas co-overexpression of CXCR4 and αvß6 was an independent prognostic factor only for OS (p = 0.043). CONCLUSION: CXCR4 and αvß6 may play synergistic roles in the progression of BC, and co-targeting of CXCR4 and αvß6 could be a potential strategy for the prevention and treatment of BC.

A study on the biological function of heat shock factor 1 proteins in breast cancer.

The present study aimed to investigate the effect of HSF1 proteins on cell proliferation, apoptosis and invasion of breast cancer. The Michigan Cancer Foundation-7 (MCF-7) HSF1-knocked down stable cell line (experimental group) and control cell line (control group) were obtained using a lentivirus assay, and the effects of HSF1 knockdown on the proliferation, tumor formation, apoptosis and invasion ability were analyzed, respectively. The effects of HSF1 on downstream signals were analyzed using western blotting. Western blotting results showed that lentivirus successfully established a HSF1 knockdown stable cell line of MCF-7. Compared with the control group, the growth rate of MCF-7 cells in the experimental group was significantly decreased (P<0.05). Flow cytometry showed that the proportion of apoptosis in the control group was significantly lower than that of the experimental group (P<0.05). Notably, the invasion ability of cells in the control group was significantly higher than that in the experimental group (P<0.05). Compared with cells in the control group, the levels of heat shock protein (HSP)70, HSP90, anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) and macrophage migration inhibitory factor (MIF) in the experimental group were significantly downregulated, whereas the level of Bax was significantly increased (P<0.05). In conclusion, HSF1 protein, as a transcription factor, regulates the expression levels of HSP70, HSP90, MIF, Bcl-2 and Bax, thus controlling the proliferation, apoptosis and invasion of cells. These findings suggest HSF1 protein as a potential target for the treatment of breast cancer.

A study on the biological function of heat shock factor 1 proteins in breast cancer.

The present study aimed to investigate the effect of HSF1 proteins on cell proliferation, apoptosis and invasion of breast cancer. The Michigan Cancer Foundation-7 (MCF-7) HSF1-knocked down stable cell line (experimental group) and control cell line (control group) were obtained using a lentivirus assay, and the effects of HSF1 knockdown on the proliferation, tumor formation, apoptosis and invasion ability were analyzed, respectively. The effects of HSF1 on downstream signals were analyzed using western blotting. Western blotting results showed that lentivirus successfully established a HSF1 knockdown stable cell line of MCF-7. Compared with the control group, the growth rate of MCF-7 cells in the experimental group was significantly decreased (P<0.05). Flow cytometry showed that the proportion of apoptosis in the control group was significantly lower than that of the experimental group (P<0.05). Notably, the invasion ability of cells in the control group was significantly higher than that in the experimental group (P<0.05). Compared with cells in the control group, the levels of heat shock protein (HSP)70, HSP90, anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) and macrophage migration inhibitory factor (MIF) in the experimental group were significantly downregulated, whereas the level of Bax was significantly increased (P<0.05). In conclusion, HSF1 protein, as a transcription factor, regulates the expression levels of HSP70, HSP90, MIF, Bcl-2 and Bax, thus controlling the proliferation, apoptosis and invasion of cells. These findings suggest HSF1 protein as a potential target for the treatment of breast cancer.

Alterations in hormonal receptor expression and HER2 status between primary breast tumors and paired nodal metastases: discordance rates and prognosis.

BACKGROUND: We aimed to evaluate the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression discordance in matched pairs of primary breast cancer and lymph node metastasis specimens and determine the effect of discordance on prognosis. MATERIALS AND METHODS: Among all patients diagnosed with lymph node metastases from 2004 to 2007, primary tumors and paired lymph node metastases were resected from 209 patients. The status of ER, PR, and HER2 expression was analyzed immunohistochemically in 200, 194, and 193 patients, respectively. Discordance was correlated with prognosis. RESULTS: Biomarker discordance between primary tumors and paired lymph node metastases was 25.0% (50/200) for ER status, 28.9% (56/194) for PR status, and 14.0% (27/193) for HER2 status. ER positivity was a significant independent predictor of improved survival when analyzed in primary tumors and lymph node metastases. Patients with PR-positive primary tumors and paired lymph node metastases displayed significantly enhanced survival compared to patients with PR-positive primary tumors and PR-negative lymph node metastases. Patients with ER- and PR-positive primary tumors and paired lymph node metastases who received endocrine therapy after surgery displayed significantly better survival than those not receiving endocrine therapy. Similalry treated patients with PR-negative primary tumors and PR-positive paired lymph node metastases also displayed better survival than those not receiving endocrine therapy. CONCLUSIONS: Biomarker discordance was observed in matched pairs of primary tumors and lymph node metastases. Such cases displayed poor survival. Thus, it is important to reassess receptor biomarkers used for lymph node metastases.