The epigenetic regulators EP300/CREBBP represent promising therapeutic targets in MLL-rearranged acute myeloid leukemia.

Acute myeloid leukemia (AML) with mixed-lineage leukemia (MLL) gene rearrangements (MLL-r) is an aggressive subtype of blood cancer with dismal prognosis, underscoring the urgent need for novel therapeutic strategies. E1A-binding protein (EP300) and CREB-binding protein (CREBBP) function as essential transcriptional coactivators and acetyltransferases, governing leukemogenesis through diverse mechanisms. Targeting EP300/CREBBP holds great promise for treating leukemia with some certain cytogenetic abnormalities. Here, we demonstrated that EP300 and CREBBP are core epigenetic regulators in the pathogenesis of MLL-r AML through assaying the transposase-accessible chromatin with high-throughput sequencing (ATAC-seq). Knocking-out EP300/CREBBP and inhibitor (A-485) treatment depressed the MLL-r cells proliferation, while the MLL wild-type cells remained uninfluenced. We found that the CDK4/RB/E2F axis was downregulated specifically in MLL-r AML cell after A-485 treatment by RNA-seq, western blot and cut-tag analyses. EP300/CREBBP inhibitor selectively exerted potent anti-leukemia activity through blocking the MLL-r-BET complex binding to H3K27Ac modification on critical genes loci, distinct from global histone acetylation. Collectively, our study identified EP300/CREBBP as a critical epigenetic driver of MLL-r leukemia and validated their therapeutic potential through targeting inhibition, offering a promising avenue for improving clinical outcomes in this aggressive leukemia.

Receptor conversion impacts outcomes of different molecular subtypes of primary breast cancer.

BACKGROUND: Although the conversion of clinically used breast cancer biomarkers such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) between primary tumors and metastatic lesions is well recognized, data on whether receptor conversion has an effect on therapy management and survival in patients with metastatic breast cancer is limited. This study aimed to investigate the clinical implications of receptor conversion throughout tumor progression. METHODS: In total, 2450 patients diagnosed with metastatic breast cancer in Tianjin Medical University Cancer Institute and Hospital were analyzed and 426 female patients with available biopsy results from both primary and metastatic sites were included in this study. We investigated the alteration of ER, PR and HER2 during breast cancer progression and evaluated the therapy management and prognostic value of receptor conversion. RESULTS: The conversion rates of ER, PR, and HER2 between primary tumors and metastasis were 21.1% (McNemar's test p < 0.001), 33.2% (p < 0.001), and 11.6% (p = 0.868), respectively. Evaluation of ER, PR, and HER2 status in multiple consecutive metastases revealed a change in 19.1% (p > 0.05), 23.5% (p = 0.021), and 9.8% (p > 0.05) of patients, respectively. Adjuvant therapy (chemotherapy/endocrine therapy) was related to hormone receptor conversion (p < 0.05). A statistically significant differential survival associated with hormone receptor (ER/PR) conversion (log-rank p < 0.05) was observed. In the multivariate analysis, ER conversion was an independent influence factor of survival (p < 0.05). Molecular typing conversion in primary and metastatic lesions also had a significant effect on survival (p < 0.05). We found that changing treatment based on the receptor conversion could affect clinical outcomes (p < 0.05). CONCLUSIONS: Our findings indicated that receptor conversion during breast tumor progression had a significant effect on survival. Most importantly, our findings proved that patients with receptor conversion benefited from a change in therapy.

HAND2-AS1 Works as a ceRNA of miR-3118 to Suppress Proliferation and Migration in Breast Cancer by Upregulating PHLPP2.

Large quantities of long noncoding RNAs (lncRNAs) have been verified to exert vital functions in the process of breast cancer (BC). lncRNA heart and neural crest derivatives expressed 2-antisense RNA 1 (HAND2-AS1) was reported to suppress the development of several cancers. However, its detailed function in BC remained unclear. In the current study, HAND2-AS1 was discovered to be low expressed in BC cell lines, and overexpression of HAND2-AS1 could repress proliferation, migration, and invasion but facilitate apoptosis in BC cells. Moreover, HAND2-AS1 was found to act as a sponge of miR-3118 which was detected to be upregulated in BC cell lines. miR-3118 depletion could constrict the progression of BC. HAND-AS1 hindered the course of BC by reducing the expression of miR-3118. Besides, PHLPP2 was treated as a downstream target of miR-3118 under the selection of RNA pull-down assays. HAND2-AS1 inhibited the process of BC by enhancing expression of PHLPP2. In summary, our study testified that HAND2-AS1 suppressed BC growth by targeting the miR-3118/PHLPP2 axis, indicating that HAND2-AS1 could be regarded as a potential target for BC treatment.

FBXL19-AS1 promotes cell proliferation and inhibits cell apoptosis via miR-876-5p/FOXM1 axis in breast cancer.

As the most common cancer and one of the leading causes of cancer-associated mortality, breast cancer continues to need more key molecules to regulate its progression. F-box and leucine-rich repeat protein 19 antisense RNA 1 (known as FBXL19-AS1) is a long non-coding RNA (lncRNA) which has been reported as an oncogene in several types of human cancers. However, the specific downstream targets of FBXL19-AS1 remain unknown. In this study, we set out to find more reliable downstream molecules of FBXL19-AS1 in breast cancer. FBXL19-AS1 was expressed at a high level in breast cancer cells. Loss-of-function experiments revealed that silencing FBXL19-AS1 could impair cell proliferation and induce cell apoptosis in breast cancer. In addition, the location of FBXL19-AS1 in the cytoplasm was detected by fluorescent in situ hybridization assay, while FBXL19-AS1 regulated the expression of Forkhead box M1 (FOXM1) by directly absorbing miR-876-5p. Through rescue assays, it was observed that FOXM1 overexpression recovered the inhibited tumor growth caused by FBXL19-AS1 downregulation. We affirmed the function of FBXL19-AS1 in breast cancer and described the mechanism of the FBXL19-AS1/miR-876-5p/FOXM1 axis. The current work presents the molecular mechanism which underlies FBXL19-AS1 in breast cancer and suggests a comprehensive, feasible FBXL19-AS1-mediated therapeutic approach for treating breast cancer.

Aberrant Regulation of RAD51 Promotes Resistance of Neoadjuvant Endocrine Therapy in ER-positive Breast Cancer.

Breast cancer is one of the most common malignant cancers affecting females. Estrogen receptor (ER)-positive breast cancer is responsive to endocrine therapy. Although current therapies offer favorable prospects for improving survival, the development of resistance remains a severe problem. In this study, we explored the resistance mechanisms of ER-positive breast cancer to neoadjuvant endocrine therapy. Microarray data of GSE87411 contained 109 pairs of samples from Z1031 trial, including untreated samples and post-treated samples with neoadjuvant aromatase inhibitor (AI) therapy. The differentially expressed genes (DEGs) were obtained from two different comparisons: untreated samples versus post-treated samples with AIs, and post-treated samples sensitive versus resistant to AIs. Multiple bioinformatic methods were applied to evaluate biological function, protein-protein network and potential binding between target protein and aromatase inhibitor. Then, regulation of gene expression, DNA methylation and clinicopathological factors of breast cancer were further analyzed with TCGA data. From GSE87411 dataset, 30 overlapped DEGs were identified. Cell division was found to be the main function of overlapped DEGs by functional enrichment and gene ontology (GO) analysis. RAD51 recombinase (RAD51), a key protein of homologous recombination, was detected to interact with BReast CAncer genes 2 (BRCA2). Moreover, according to the docking simulation, RAD51 might potentially bind to AIs. Overexpressed RAD51 was associated with hypermethylation of BRCA2, resistance to AIs and poor overall survival of patients with ER-positive breast cancer. Furthermore, RAD51 was found to be a better indicator than MKI67 for predicting resistance in neoadjuvant setting. The results indicated that methylation of BRCA2 led to incomplete suppression on RAD51, which caused an increased expression of RAD51, subsequently AI-resistance and poor prognosis in ER-positive breast cancer. RAD51 could be a new candidate used as a predicative marker and therapeutic target in neoadjuvant endocrine treatment.

The comparison of maintenance treatment with capecitabine (CMT) and non-maintenance treatment with capecitabine (non-CMT) in patients with metastatic breast cancer.

AIM: The study examined the response rate, response duration and toxicity of maintenance treatment (CMT) and non-maintenance treatment with capecitabine (non-CMT) in metastatic breast cancer (MBC). MATERIAL AND METHODS: Between September 2009 and July 2013, a group of 82 patients with MBC, who had progressed after anthracycline/taxane chemotherapy, was treated with a capecitabine-based chemotherapy and divided into two groups. 54 patients received CMT 1.5 g twice a day from days 1 to 14, and 28 patients achieved non-CMT. Treatment was continued until disease progression or unacceptable toxicity. The median age of patients treated with CMT and non-CMT was 57 years (range 38-78) and 50 years (range 37-77). The evaluation of treatment effect was possible in all patients. RESULTS: The overall response rate (ORR) was 29.7% (16 cases), including 3 (5.6%) complete responses (CR) and 13 (24.1%) partial responses (PR). Stable disease (SD) was observed in 7.4% of patients receiving CMT (54 patients). In the group receiving non-CMT, ORR was 3.6% (1 case). The median PFS in CMT group was 36 weeks, while in non-CMT group was 24 weeks. The most common adverse event was hematologic toxicity (74.1%), with the incidence of grade 1-2/3-4 was 70.4% and 3.7%. Hand-foot syndrome was the most frequent non-hematologic form of toxicity, occurring in 70.4% of cases. There were no treatment-related deaths. CONCLUSIONS: CMT is an effective and safe treatment for pretreated metastatic breast cancer patients. And CMT appears to be a more efficacious treatment than non-CMT.

Analysis of Clinical Features and Outcome of 356 Triple-Negative Breast Cancer Patients in China.

BACKGROUND: The purpose of this study was to investigate the clinicopathological features and analyze the prognostic factors of triple-negative breast cancer (TNBC). PATIENTS AND METHODS: The clinical data of 1,788 breast cancer patients was collected and analyzed. The Kaplan-Meier method was used to estimate survival. Multivariate analysis of the prognostic factors for survival was performed using the Cox regression model. RESULTS: Patients with TNBC exhibited characteristics significantly differing from those with non-TNBC. There was a higher proportion of patients with age < 35 years, stage III disease, tumor size > 5 cm, lymph node positivity, and histological grade 3. The 5-year disease-free survival (DFS) rates of TNBC and non-TNBC patients were 75.7 and 79.6%, respectively (p < 0.05). 5-year overall survival (OS) was 86.6 and 93.5%, respectively (p < 0.05). In multivariate Cox regression analysis, the independent prognostic factors for shorter DFS were age < 35 years (hazard ratio (HR) 2.105), positive lymph nodes (HR 7.039), histological grade 3 (HR 1.841), and for shorter OS positive lymph nodes (HR 4.626). CONCLUSION: The proportion of TNBC in breast cancer in China is higher than in other areas. TNBC is correlated with younger age, larger tumor size, positive lymph nodes, higher clinical stage and histological grade, and lower DFS and OS, which is consistent with previous reports.

[Docetaxel and capecitabine combination chemotherapy for patients with anthracycline-resistant metastatic breast cancer].

OBJECTIVE: To evaluate the efficacy and safety of docetaxel and capecitabine combination chemotherapy (DC regimen) for patients with anthracycline-resistant metastatic breast cancer. METHODS: Thirty-two patients with anthracycline-resistant metastatic breast cancer were treated with a docetaxel and capecitabine combination regimen. All patients received oral administration of capecitabine at a dose of 1250 mg/m(2) twice daily, within 30 min after meal on D1 to D14, and intravenous infusion of docetaxel at a dose of 75 mg/m(2) on D1. The regimen was repeated every 3 weeks. RESULTS: A total of 126 cycles of DC regimen were administered in the 32 cases, with a median of 4 cycles. The overall response rate was 46.9%. Among the 32 patients, there were complete response in 1, partial response in 14, stable disease in 11 and progressive disease in 6 cases. The median time to progression (TTP) was 5.6 months. The one-year survival rate was 56.3%. The effective cases in different metastatic organs were: 8 cases in the lung, 6 cases in the liver, 3 cases in the soft tissue and 3 cases in the lymph nodes. The common adverse reactions were myelosuppression, hand-foot syndrome, nausea and vomiting. Neutropenia was observed in 84.4% of the patients. Two patients developed degree IV myelosuppression. CONCLUSION: The combination chemotherapy regimen of docetaxel plus capecitabine is well-tolerated and effective for anthracycline-resistant metastatic breast cancer.