Dan Xie

Hormone receptor positive (HR-positive) breast cancer (BC) is the most common subtype of breast cancer. Despite adjuvant endocrine therapy and chemotherapy-based treatment, the therapeutic response is often not satisfactory in HR-positive BC patients. Therefore, elucidating the mechanisms that regulate the progression of HR-positive BC is urgently required to identify new therapeutic targets. Previously, HLA Complex Group 11 (HCG11), located on the major histocompatibility complex (MHC) region, was found to be abnormally expressed in a variety of tumor cells. However, the role of HCG11 in HR-positive BC cells has not been explored to date. In the current study, we found that HCG11 is downregulated in HR-positive BC tissues and cell lines. Both in vitro and in vivo, HCG11 acts as a tumor suppressor in HR-positive BC cells. Furthermore, the mechanistic details unraveled that HCG11 recruits Serine/arginine-rich splicing factor 1 (SRSF1) to target β-catenin mRNA for promoting the translation of β-catenin. Our study emphasizes the potential of HCG11 as a novel intervention target for HR-positive BC treatment.

Triple‐negative breast cancer (TNBC) is the most aggressive subtypes of breast cancer, which has few effective targeted therapies. Various sources of evidence confirm that microRNAs (miRNAs) contribute to the progression and metastasis of human breast cancer. However, the molecular mechanisms underlying the changes in miRNAs expression and the regulation of miRNAs functions have not been well clarified. In this study, we found that the expression of miR‐30b‐5p was upregulated in breast cancer tissues and breast cancer cell lines, compared to paracancer tissues and normal breast cell lines. Moreover, induced overexpression of miR‐30b‐5p promoted the MDA‐MB‐231 and HCC 1937 cell growth, migration, and invasion and reduced the cellular apoptosis. Further studies confirmed that miR‐30b‐5p could directly target ASPP2 and then activate the AKT signaling pathway. Our results suggested that miR‐30b‐5p could act as a tumor promoter in TNBC. The newly identified miR‐30b‐5p/ASPP2/AKT axis represents a novel therapeutic strategy for treating TNBC.

Hongming Song, Dengfeng Li, Tianqi Wu, Dan Xie, Kaiyao Hua, Jiashu Hu, Xiaochong Deng, Changle Ji, Yijun Deng, and Lin Fang. BMB Reports 2018;51:602-7. https://doi.org/10.5483/BMBRep.2018.51.11.168

The aim of the present study was to define the function of microRNA‑424‑5p (miR‑424) in breast cancer cells. The present study investigated the level and the potential function of miR‑424 in breast cancer by reverse transcription‑quantitative polymerase chain reaction assays. miR‑424 expression was decreased in the majority of human breast cancer specimens and cell lines used in the present study. The MTT assay, plate colony formation assay and flow cytometry analyses were used to characterize the function of miR‑424 in two types of breast cancer cell lines. Upregulation of miR‑424 inhibited cellular proliferation and regulated the cell cycle by arresting cells in the G2/M cell phase. The dual‑luciferase reporter assay was used to confirm the direct association between miR‑424 and cyclin‑dependent kinase 1 (CDK1). Silencing of CDK1 expression by CDK1 short interfering RNA also significantly suppressed cell proliferation and arrested cells in the G2/M cell phase. The results of the present study indicated that miR‑424 can suppress cell proliferation and arrest cells in G2/M cell phase by negatively regulating CDK1 mRNA in human breast cancer, possibly through the Hippo pathway and the extracellular signal‑regulated kinase pathway. The results of the present study provided novel evidence for the role of miR‑424 in breast cancer.

Background/Aims: Dysregulated expression of WW domain-binding protein 2 (WBP2) is associated with poor prognosis in ER+ breast cancer patients. However, its role in triple negative breast cancer (TNBC) has not been previously assessed. Therefore, we aimed to elucidate the functional mechanism of WBP2 in TNBC cells. Methods: qRT-PCR, western blotting, and immunohistochemical staining were used to evaluate WBP2 expression in TNBC patient tumors and cell lines. HCC1937 and MDA-MB-231 cells transiently transfected with WBP2 small interfering RNA (siRNA), miR-613 mimics, or miR-613 inhibitors were subject to assays for cell viability, apoptosis and cell cycle distribution. Co-immunoprecipitation, western blotting or qRT-PCR were employed to monitor changes in signaling pathway-related genes and proteins. Luciferase assays were performed to assess whether WBP2 is a direct target of miR-613. The effect of miR-613 on tumor growth was assessed in vivo using mouse xenograft models. Results: The expression of WBP2 was upregulated in TNBC tissues and cells. Expression of WBP2 was significantly correlated with Ki67 in TNBC patients. Knockdown of WBP2 inhibited cellular proliferation, promoted apoptosis, and induced cell cycle arrest of TNBC cells. miR-613 directly bound to the 3’-untranslated region (3’-UTR) of WBP2 and regulated the expression of WBP2. Moreover, miR-613 reduced the expression of WBP2 and suppressed tumor growth of TNBC cells in vivo. Knockdown of WBP2 inhibited YAP transcription and the EGFR/PI3K/Akt signaling pathway in TNBC cells, and these effects were reversed by inhibition of miR-613. Conclusion: WBP2 overexpression is associated with the poor prognosis of TNBC patients and the miR-613-WBP2 axis represses TNBC cell growth by inactivating YAP-mediated gene expression and the EGFR/PI3K/Akt signaling pathway.

Apoptosis-stimulating p53 protein 2 (ASPP2) is an apoptosis inducer that acts via binding with p53 and then enhancing the transcriptional activities toward pro-apoptosis genes. ASPP2 has recently been reported to serve a major role in p53-independent pathways. Triple-negative breast cancer (TNBC) is a type of breast cancer that is more aggressive and highly lethal when p53 is mutated. In the present study, the mRNA level of ASPP2 was found to be suppressed in breast tumors compared with that in adjacent normal breast tissues, and the expression of ASPP2 was also decreased in a series of breast cancer cell lines compared with that in MCF-10A normal breast cells. Downregulation of ASPP2 by specific small interfering RNA (siRNA) transfection was able to promote cell growth, reduce cell apoptosis, and contribute to cell migration and invasion. Furthermore, downregulation of ASPP2 promoted cell epithelial-mesenchymal transition (EMT) in MDA-MB-231 and HCC-1937 TNBC cells. Furthermore, it was found that when ASPP2 siRNA was transfected into MDA-MB-231 and HCC-1937 cells, the expression of phosphoinositide-3-kinase regulatory subunit 1 (p85 alpha) decreased and phosphorylation of protein kinase B (AKT) increased, which are key molecular regulators in the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. In conclusion, the present data indicated that ASPP2 had a crucial influence on the proliferation and metastasis in TNBC, and that the functional mechanism may be p53indepen-dent to a great extent. ASPP2 and its link with the PI3K/AKT pathway deserve further investigation and may provide novel insights into therapeutic targets for TNBC.

Breast cancer is the most common female cancer in women, and its estrogen receptor (ER)-negative subtype (ENBC) and triple-negative subtype (TNBC) have unfavorable prognosis in comparison with ER-positive subtype. MiRNAs are small noncoding RNAs that bind to the 3′-UTR region of targeting mRNAs to regulate gene expression. Mir-519d-3p was found to be associated with breast cancer for its potential role in proliferation and metastasis. To explore its potential role and mechanism of miR-519d-3p in breast carcinogenesis, we determined whether miR-519d-3p regulates breast cancer cell proliferation and motility by performing wound-healing assays and migration–invasion assays. We found that miR-519d-3p significantly inhibits proliferation and motility of ENBC and TNBC cells. Overexpression of miR-519d-3p arrested breast cancer cells in the G0/G1 phase and reduced the expression of CDK4, 6/Cyclin D1, and CDK2/Cyclin E1. It was reported that miR-519d-3p or miR-519d-3p expression was associated with cancer metastasis and clinical staging. Since LIM domain kinase 1 (LIMK1) was highly expressed in breast cancer and a major regulator of breast cancer growth and metastasis, we further demonstrated that LIMK1 is a potential target of miR-519d-3p by dual-luciferase report assay. Mir-519d-3p decreases LIMK1 expression at mRNA and protein levels, and the protein level and phosphorylation of cofilin 1 (CFL1), one of the key downstream targets of LIMK1. Our findings suggest that miR-519d-3p regulates the LIMK1/CFL1 pathway in breast cancer and this new venue could be targeted for future breast cancer therapy.

Breast cancer is the most frequently diagnosed female cancer.

Breast cancer is the most common cancer in women worldwide. Triple-negative breast cancer is one of the most aggressive types of breast cancer as it has the worst clinical outcome for patients. microRNAs are a type of small non-coding RNA and play an important role in breast cancer. The purpose of this study was to explore the potential function and mechanism of miR-143-3p in triple-negative breast cancer (TNBC). MTT and colony formation assays, the effect of miR-143-3p modulation on MDA-MB-231 cell proliferation, revealed that increased miR-143-3p expression inhibited the proliferation of MDA-MB-231 TNBC cells. Moreover, miR-143-3p overexpression inhibited the movement of MDA-MB-231 TNBC cells in wound healing and transwell assays. To identify a potential miR-143-3p target, we investigated the effect of miR-143-3p modulation on LIMK1 expression level. Increased miR-143-3p expression caused a reduction in LIMK1 mRNA and protein, suggesting that LIMK1 is a target of miR-143-3p. In addition, dual-luciferase reporter assays showed that LIMK1 is a target gene of miR-143-3p. Flow cytometry analysis indicated that miR-143-3p arrested MDA-MB-231 TNBC cells at the G0/G1 phase. The TCGA (The Cancer Genome Atlas) database demonstrated that miR-143-3p was down-regulated in breast cancer tissues compared with normal breast tissues. These data demonstrated that miR-143-3p functioned as a suppressor gene in TNBC and that miR-143 targeted therapy may be a new strategy for TNBC treatment.