The Novel Transcription Factor CREB3L4 Contributes to the Progression of Human Breast Carcinoma.

Breast carcinoma(BC)is the most common cancer type among females globally. Understanding the molecular pathways that trigger the development of BC is crucial for both prevention and treatment. As such, the role of transcription factors (TFs) in the development of BC is a focal point in this field. CREB3s play a critical role in initiating the unfolded protein response (UPR); however, the role of CREB3 family members in breast cancer development remains largely unknown. Here, we mined the ONCOMINE database for the transcriptional data of CREB3s in patients with BC. Then, the regulatory functions of a novel TF, CREB3L4, were investigated. CREB3L4 knockdown in MDA-MB-231 and MCF-7 cells suppressed proliferation and promoted apoptosis and cell cycle arrest. ChIP assays confirmed that CREB3L4 can directly bind to the PCNA promoter region, suggesting that the PCNA protein may be functionally downstream of CREB3L4. Additionally, the expression level of CREB3L4 was assessed using our cohort. CREB3L4 is upregulated in breast cancer tissues and is significantly associated with histological grade and tumour size (P = 0.001 and P < 0.001, respectively). Furthermore, PCNA expression was upregulated in breast cancer tissues and positively correlated with CREB3L4. In summary, CREB3L4 may play an important role in the progression of human BC and may serve as a therapeutic target.

Tumor suppressor OTUD3 induces growth inhibition and apoptosis by directly deubiquitinating and stabilizing p53 in invasive breast carcinoma cells.

BACKGROUND: P53 pathway inactivation plays an important role in the process of breast cancer tumorigenesis. Post-translational protein modification abnormalities have been confirmed to be an important mechanism underlying inactivation of p53. Numerous deubiquitinating enzymes are aberrantly expressed in breast cancer, and a few deubiquitination enzymes can deubiquitinate and stabilize p53. Here, we report that ovarian tumor (OTU) deubiquitinase 3 (OTUD3) is a deubiquitylase of p53 in breast carcinoma (BC). METHODS: Correlations between the mRNA expression levels of OTUD3, TP53 and PTEN and the prognosis of BC were assessed with the Kaplan-Meier Plotter tool. OTUD3 protein expression in 80 pairs of specimens in our cohort was examined by immunohistochemistry and western blotting. The relationship among OTUD3, p53, and p21 proteins was analyzed. Half-life analysis and ubiquitylation assay were performed to elucidate the molecular mechanism by which OTUD3 stabilizes p53. The interaction between OTUD3 and p53 in BC cells was verified by a co-immunoprecipitation assay and GST pulldown experiments. MTS assay for proliferation detection, detection of apoptosis induced by cisplatin and colony formation assay were employed to investigate the functional effects of OTUD3 on breast cancer cells. RESULTS: OTUD3 downregulation is correlated with a poor prognosis in BC patients. OTUD3 expression is decreased in breast cancer tissues and not associated with the histological grade. OTUD3 also inhibits cell proliferation and clone formation and increases the sensitivity of BC cells to apoptosis induced by chemotherapy drugs. Reduced OTUD3 expression accompanied by decreased p53 abundance is correlated with human breast cancer progression. Ectopic expression of wild-type OTUD3, but not its catalytically inactive mutant, stabilizes and activates p53. Mechanistically, OTUD3 interacts directly with p53 through the amino-terminal OTU region. Finally, OTUD3 protects p53 from murine double minute 2 (Mdm2)-mediated ubiquitination and degradation, enabling the deubiquitination of p53 in BC cells. CONCLUSIONS: In summary, we found that OTUD3 may be a potential therapeutic target for restoring p53 function in breast cancer cells and suggest that the OTUD3-p53 signaling axis may play a critical role in tumor suppression.

[Analysis of correlation between breast cancer molecular subtypes and prognosis of patients receiving breast-conserving therapy].

OBJECTIVE: To evaluate the effects of molecular subtypes on the prognosis of breast cancer patients after BCT (breast-conserving therapy). METHODS: From January 1999 to December 2007, a total of 699 female patients on BCT were analyzed retrospectively. They were grouped according to the results of immunohistochemistry, they were grouped as Luminal A (ER+/PR+/HER2-, Ki-67 < 14%), Luminal B (ER+/PR+/HER2 ± , Ki-67 > 14%), HER2 (ER-/PR-/HER2+) and triple negative breast cancer (TNBC) (ER-/PR-/HER2-). RESULTS: Among them, the recurrence rate, metastasis rate and survival rate within 5 years after BCT accounted for 6.0%, 6.0% and 91.8% respectively. There were statistical differences in metastasis rate and survival rate among patients with different molecular subtypes (P < 0.001), lymph node status (P < 0.001) and on chemotherapy or not (P < 0.001) on multivariate analysis. Though, on univariate analysis, different molecular subtypes had different risks for local failure (P = 0.022). On multivariate analysis, this difference was not statistically significant (P = 0.081). CONCLUSION: Despite a worse prognosis of TNBC versus other subtypes, BCT is a viable option for selected TNBC patients.