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Phase separation (PS) is a fundamental principle in diverse life processes including immunosurveillance. Despite numerous studies on PS, little is known about its dissolution. Here, it is shown that oleic acid (OA) dissolves the cyclic GMP–AMP synthase (cGAS)–deoxyribonucleic acid (DNA) PS and inhibits immune surveillance of DNA. As solvent components control PS and metabolites are abundant cellular components, it is speculated that some metabolite(s) may dissolve PS. Metabolite‐screening reveals that the cGAS–DNA condensates formed via PS are markedly dissolved by long‐chain fatty acids, including OA. OA revokes intracellular cGAS–PS and DNA‐induced activation. OA attenuates cGAS‐mediated antiviral and anticancer immunosurveillance. These results link metabolism and immunity by dissolving PS, which may be targeted for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Dysregulation of the nuclear export machinery mediated by chromosomal maintenance 1 (CRM1, also known as exportin‐1), is closely associated with various human disorders, such as breast cancer. Previously, we identified sulforaphene and its synthetic analogues as covalent inhibitors of CRM1. Herein, we describe the discovery and biological evaluation of another sulforaphene synthetic analogue, LFS‐31, as a potential CRM1 inhibitor. In addition, we investigated the reversible binding mechanism of LFS‐31 with CRM1 through molecular simulations coupled with bio‐layer interferometry (BLI) and found relatively high binding affinity (KD = 43.1 ± 35.3 nM) between the LFS‐31 and CRM1 groups. We found that LFS‐31 exhibited a stronger growth suppression of triple‐negative breast cancer (TNBC) cells than non‐TNBC cells, and had minimal effect on normal breast cells. Pharmacological treatment of TNBC cells with LFS‐31 at nanomolar concentrations led to the nuclear retention of IkBα resulting in strong suppression of NF‐κB transcriptional activity and attenuated cell growth and proliferation, which collectively contributed to the antitumor responses. To the best of our knowledge, this is the first study to demonstrate the use of a sulforaphene analogue as a potent CRM1 inhibitor that targets the NF‐κB signaling pathway for the targeted therapy of TNBC. [ABSTRACT FROM AUTHOR]

Lipase member H (LIPH), a novel member of the triglyceride lipase family. The clinical implications of its expression in breast cancer are still unclear. Therefore, in this study, we investigated the associations between LIPH and the tumorigenic behaviours of 144 triple‐negative breast cancer (TNBC) patients. The ratio and mammosphere‐forming ability of CD44+/CD24− stem‐like cells were tested. The role of LIPH in breast cancer cell migration and invasion was also evaluated. In addition, the effect of LIPH silencing on mitochondrial respiration was determined using the Seahorse assay. Finally, the effect of LIPH silencing on protein expression was determined via tandem mass tag‐based spectrometry and Western blotting. We found that LIPH expression was associated with metastasis in lymph nodes and distant organs (P = 0.025), resulting in poor survival among breast cancer patients (P = 0.027). LIPH knockdown significantly decreased both the ratio of CD44+/CD24− stem‐like cells and their mammosphere‐forming ability. LIPH silencing promoted apoptosis, arrested cell cycle in the G2/M phase, mitigated the oxidation‐related oxygen consumption rate in the mitochondria, and reduced metabolism. LIPH inhibited adhesion between tumour cells and enhanced the epithelial‐mesenchymal transition. Tandem mass spectrometric analysis presented 68 proteins were differentially expressed in LIPH‐silenced cells and LIPH‐mediated modulation of tumour cell adhesion depended on integrin‐related CAPN2 and paxillin signalling. Overall, our findings provided strong evidence that LIPH up‐regulation promoted metastasis and the stemness of TNBC cells. Therefore, targeting LIPH is a potentially viable strategy for preventing metastasis in TNBC. [ABSTRACT FROM AUTHOR]

Endothelin receptor B (EDNRB) is one of the receptors in the endothelin axis and its upregulated expression is associated with tumorigenesis and metastasis of several types of solid tumors. However, the expression profile of EDNRB in breast cancer and its role in the progression of breast cancer are unclear. Here, we show that EDNRB expression is higher in metastatic tumors than in primary breast cancer, and is associated significantly with lymph node metastasis and poor survival in Chinese patients with breast cancer. EDNRB expression was particularly upregulated in triple‐negative breast cancer (TNBC) cells. Moreover, EDNRB silencing by a specific shRNA significantly attenuated the proliferation, migration, and invasiveness of MDA‐MB‐231 and BT549 cells and increased their apoptosis, as well as retarded the growth of implanted tumors in mice. Tandem mass spectrometry analysis indicated that 248 proteins were differentially expressed in EDNRB‐silenced cells and their cellular organelles, and these proteins participate in many processes. EDNRB silencing decreased protein kinase B and extracellular regulated protein kinase phosphorylation and promoted the mesenchymal‐to‐epithelial transition process in MDA‐MB‐231 cells. Therefore, our findings provide strong evidence for the first time that knockdown of EDNRB expression inhibits the progression of TNBC and that EDNRB can serve as a prognostic biomarker and therapeutic target for the treatment of TNBC. [ABSTRACT FROM AUTHOR]

Staphylococcal nuclease domain‐containing 1 (SND1) expression is crucial for breast cancer metastasis; however, the clinical implications of SND1 expression in breast cancer remain unclear. This study investigated the relationship of SND1 protein expression both with metastasis and the prognoses of 144 breast cancer patients over a 10‐year follow‐up. Chi‐square tests revealed that the percentages of positive SND1 expression in breast cancer tumors were significantly associated with larger tumor size (>2 cm, P = 0.043), higher clinical TNM stage (P = 0.003), and positive lymph node metastasis (P = 0.001). Breast cancer patients with positive SND1 expression had a significantly shorter overall survival and disease‐free survival than those with negative SND1 expression (P < 0.01). Multiple Cox regression analysis indicated that SND1 expression is an independent risk factor for shorter disease‐free survival (hazard ratio = 1.97, P = 0.014). The percentages of SND1 expression in metastatic breast cancers were significantly higher than that in primary tumors in 30 patients with advanced breast cancer (P = 0.016). Therefore, SND1 protein expression is significantly associated with breast cancer metastasis and may serve as a biomarker for prognosis of breast cancer patients. Staphylococcal nuclease domain‐containing 1 (SND1) expression is crucial for breast cancer metastasis; however, the clinical implications of SND1 expression in breast cancer remain unclear. Examining 144 breast cancer patients over a 10‐year follow‐up, this study found that SND1 protein expression is significantly associated with breast cancer metastasis, and may serve as a biomarker for the prognosis of breast cancer patients. [ABSTRACT FROM AUTHOR]

( Cancer Sci 2010; 101: 815–819) Recently, it was observed that nestin is preferentially expressed in basal/myoepithelial cells of the mammary gland, and that this intermediate filament may be used as a myoepithelial marker. However, the clinical and prognostic implications of nestin as a marker for breast cancer are still unclear. We examined mastectomy specimens from 150 breast cancers and matching, adjacent non-cancerous tissues using immunohistochemistry and western blotting. Overall, triple-negative breast cancers – that is, breast cancers that do not express estrogen receptors (ER), progesterone receptors (PR), or human epidermal growth factor receptor 2 (HER2/neu) – had higher expression rates for nestin than the other breast cancers (57.14% vs 9.30%; P < 0.001). In triple-negative breast cancers, significantly increased nestin expression rates were observed in patients with lymph node metastasis compared with those without node metastasis (25.00% vs 76.92%; P = 0.032). A similar phenomenon was observed for invasive ductal carcinomas compared with ductal carcinoma in situ (16.67% vs 73.33%; P = 0.046). Nestin expression was also found to be significantly related to ER, PR, and P53 expression ( P < 0.05). Nestin expression was associated with both shorter breast cancer-specific survival and poor relapse-free survival in the lymph node-positive group ( P = 0.028 and P = 0.012 respectively). After Cox regression was carried out, nestin was not shown to be an independent prognostic factor for breast cancer. These findings substantiate the possibility of using nestin as a marker for triple-negative breast cancer. Triple-negative breast cancer progression is associated with nestin; however, the underlying mechanisms of this relationship require further investigation. [ABSTRACT FROM AUTHOR]