ABSTRACT
Over-expression of the human epidermal growth factor receptor-2 (HER2) is related to aggressive tumors and poor prognosis in breast cancer. Trastuzumab (TRA) resistance leads to tumor recurrence and metastasis, resulting in poor prognosis in HER2-positive breast cancer. POU Class 4 Homeobox 1 (POU4F1) is a member of the POU domain family transcription factors, and has a key role in regulating cancers. However, its effects on TRA-resistant HER2-positive breast cancer are still vague. In the present study, we found that POU4F1 expression was dramatically increased in clinical breast cancer specimens with TRA resistance. Higher POU4F1 was also detected in HER2-positive breast cancer cells with TRA resistance than that of the parental ones. Poor prognosis was detected in breast cancer patients with high POU4F1 expression. Under TRA treatment, POU4F1 knockdown significantly reduced the proliferative capacity of HER2-positive breast cancer cells with TRA resistance. POU4F1 silence also sensitized resistant HER-positive breast cancer cells to TRA treatment in vivo using a xenograft mouse model, along with the markedly reduced tumor growth rate and tumor weight. Moreover, we found that POU4F1 deletion greatly decreased the activation of mitogen-activated or extracellular signal-regulated protein kinase kinases 1 and 2 (MEK1/2) and extracellular-regulated kinase 1/2 (ERK1/2) signaling pathways in breast cancer cells with TRA resistance. Migration and invasion were also effectively hindered by POU4F1 knockdown in TRA-resistant HER2-positive breast cancer cells. Notably, we found that POU4F1 deletion-improved chemosensitivity of HER2-positive breast cancer cells with drug-resistance to TRA treatment was closely associated with the blockage of ERK1/2 signaling. Collectively, our findings reported a critical role of POU4F1 in regulating TRA resistance, and demonstrated the underlying molecular mechanisms in HER2-positive breast cancer. Thus, POU4F1 may be a promising prognostic and therapeutic target to develop effective treatment for overcoming TRA resistance.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Breast Neoplasms/metabolism , MAP Kinase Signaling System , Transcription Factor Brn-3A/metabolism , Trastuzumab/therapeutic use , Animals , Breast Neoplasms/drug therapy , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Movement , Cell Proliferation , Drug Resistance, Neoplasm/genetics , Female , Humans , Mice, Nude , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Neoplasm Invasiveness , Receptor, ErbB-2/analysis , Transcription Factor Brn-3A/genetics , Transcription Factor Brn-3A/physiologyABSTRACT
OBJECTIVE: The study was designed to construct and validate a nomogram for predicting overall survival (OS) of male breast cancer (MBC) patients with infiltrating duct carcinoma (IDC). METHODS: The cohort was selected from the Surveillance, Epidemiology, and End Results (SEER) database between January 1, 2004 and December 31, 2013. Univariate and multivariate Cox proportional hazard (PH) regression models were performed. A nomogram was developed based on the significant prognostic indicators of OS. The discriminatory and predictive capacities of nomogram were assessed by Harrell's concordance index (C-index), calibration plots, area under the curve (AUC) and the decision curve analysis (DCA). RESULTS: The median and maximal survival time of 1862 eligible patients were 49 and 131 months, respectively. Multivariate analysis showed that age (P < 0.0001), marital status (P = 0.002), T stage (P < 0.0001), N stage (P = 0.021), M stage (P < 0.0001), progesterone receptor (PR) (P = 0.046), human epidermal growth factor receptor-2 (HER2) (P = 0.009), and chemotherapy (P = 0.003) were independent prognostic indicators of IDC of MBC. The eight variables were then combined to construct a 3-and 5-year nomogram. The C-indexes of the nomogram were0.740 (95% confidence interval [CI] [0.709-0.771]) and 0.718 (95% CI [0.672-0.764]) for the internal validation and external validation, respectively. A better discriminatory capacity was observed in the nomogram compared with the SEER summary stage (P < 0.001) and AJCC TNM staging systems (6th edition; P < 0.001) with respect to OS prediction. Good consistency was detected between the nomogram prediction and actual findings, as indicated by calibration curves. The AUC for 3-and 5-year OS was 0.739 (95% CI [0.693-0.786]) and 0.764 (95% CI [0.725-0.803]) in the training cohort and 0.737 (95% CI [0.671-0.803]) and 0.735 (95% CI [0.678-0.793]) in the validation cohort, respectively. The DCA demonstrated that the survival nomogram was clinically useful. CONCLUSIONS: The nomogram was able to more accurately predict 3-and 5-year OS of MBC patients with IDC histology than were existing models.
ABSTRACT
OBJECTIVE: To investigate the expression of translationally controlled tumor protein (TCTP) in human breast cancer tissues and its clinical significances. METHODS: The expression of TCTP in 94 human breast cancer and the corresponding adjacent normal mammary tissues were detected using immunohistochemistry. RESULTS: The expression rate of TCTP was 64.89% in human breast cancer tissues, significantly higher than that in normal benign mammary tissues (39.36%, P<0.001). TCTP overexpression was positively correlated to the tumor size, clinical stage, lymph node metastasis and histological grade of breast cancer (P<0.05). Patients with positive TCTP expression had a significantly shorter mean survival time than those with negative expression (P<0.001). CONCLUSION: TCTP may play an important role in the tumorigenesis and development of breast cancer, and can be an important prognostic factor for this malignancy.
