Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer with poor prognosis. Despite the emergence of new and targeted therapies for other types of breast cancer, chemotherapy, surgery and radiotherapy are the only common therapies for TNBC. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), with selective apoptotic properties in tumour cells has been considered as a promising neoadjuvant therapy in some cancers including TNBC. The application of TRAIL in clinic has been prevented due to its short half-life and TRAIL resistance. More importantly, the monotherapy of TRAIL could not acquire optimal efficacy in most cases. In this study, placental-derived mesenchymal stem cells (PDMSCs) have been genetically engineered to deliver a soluble form of TRAIL at the tumour site. Curcumin-loaded chitosan nanoparticles were also fabricated to augment the apoptotic effect of TRAIL. The antitumour effects of this combination therapy were studied in vitro and in mouse models of TNBC. Results indicated that simultaneous delivery of curcumin nanoparticles and TRAIL expressing PDMSCs effectively induces apoptosis in tumour cells and significantly inhibits tumour growth in vivo. This modality may provide new cues for developing new treatment strategies for this type of breast cancer.

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Background: Metastasis is a major cause of death from cancer in triple-negative breast cancer (TNBC). Apoptosis evasion is a critical feature of metastatic tumor cells. Chemopreventive and apoptotic potential of curcumin has been shown in breast cancer. However, the precise mechanism of these effects against metastatic tumor cells has not been clearly addressed yet. Methods: 4T1 cell line was used for induction of metastatic animal model of breast cancer. Primary and metastatic tumor cells were extracted from subcutaneous tumor and lung of cancerous mice, respectively. MTT assay was used to determine the effect of curcumin on viability of tumor cells. Quantitative real-time polymerase chain reaction was performed to analyze the effect of curcumin on death receptor-5 (DR-5) gene expression. Results: Our data revealed that, compared with primary tumor cells, metastatic tumor cells were more resistance to apoptosis effects of curcumin. The DR-5 gene expression was up-regulated in both primary and metastatic tumor cells after curcumin treatment, but this up-regulation was significantly higher in primary tumor cells compared with metastatic cells. Conclusion: These findings provided important insights regarding the molecular mechanism of apoptosis resistance of metastatic tumor cells and can be used for designing a targeted therapeutic strategies in combat with metastatic TNBC.

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Background Brain metastasis is a lethal complication in triple negative breast cancer (TNBC) patients. Many factors including tumor cell molecular characteristics and biological environment are the main determinant in the brain metastasis process. Matrix metalloproteinases (MMPs) play a key role in extracellular matrix degradation, implicated in numerous aspects of metastasis processes of breast cancer. Methods After development of syngenic animal model of TNBC, primary breast cancer cells named 4T1T were isolated from tumor mass. Highly metastatic tumor cells named 4T1B were isolated and expanded from brain metastasis lesions of cancerous mice. Quantitative real-time polymerase chain reaction and gelatinase zymography were performed to analyze the expression of MMPs in transcriptomic and proteomic level in 4T1T and 4T1B. Results Our data revealed that, expression of MMPs was significantly upregulated in brain metastatic tumor cells. In transcriptomic level, MMP-2 and MMP-9 genes expression were up-regulated 4 and 3.4 folds in 4T1B, respectively. Zymographic analysis could be detect MMPs activity only in 4T1B. Conclusion These findings provided important insights regarding the gross alteration of MMPs expression in brain metastatic cascade of TNBC for the first time. Analysis of molecular properties of brain metastatic tumor cells can be used for understanding of molecular and genetic aspects of brain metastasis and also designing a targeted therapeutic strategies in combat with brain metastasis of TNBC.

Objective Osteopontin (OPN) is a well-known glycoprotein involved in numerous pathobiological processes, including cancer. Despite having five splice variants for osteopontin in mice, the main focus of most studies has been on total OPN (tOPN). There are some studies on other splice variants, but the expression of osteopontin-5 (OPN5) has not been addressed in mouse cancer cells. Therefore, this study sought to evaluate OPN5 expression in mouse breast cancer cells. Results The expression of OPN5 in primary and metastatic breast cancer cells of mice was confirmed in our study. These findings provided important insights regarding the OPN alternative splicing in mice for the first time. It is concluded that, like other OPN-SVs, OPN5 probably plays an essential role in tumor progression, which requires further investigation in different tumor models.

Objective Cancer cells having stem cell characteristics are linked to metastasis and relapse in breast cancer. Circ-Foxo3, as a circular RNA, has been linked to the breast cancer lethal traits. This study’s objective was to assess circ-Foxo3 expression in breast cancer stem-like cells. After isolation from tumor mass, breast cancer cells were subjected to the reliable in vitro assay of spheroid formation to determine the presence cancer stem cells (CSCs). We used a quantitative real-time polymerase chain reaction to examine circ-Foxo3 expression in spheroids. Results Circ-Foxo3 expression was significantly downregulated in spheroid-forming tumor cells, according to our data. This study demonstrated that breast CSCs have downregulated circ-Foxo3 expression, which may allow these cells to evade apoptosis. A precise analysis of this circRNA’s role could be exploited to develop focused therapeutic approaches to fight breast CSCs.