Therapy For Triple-negative Breast Cancer Research Articles

Targeting glutamine metabolic reprogramming of SLC7A5 enhances the efficacy of anti-PD-1 in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a heterogeneous disease that is characterized by metabolic disruption. Metabolic reprogramming and tumor cell immune escape play indispensable roles in the tumorigenesis that leads to TNBC. In this study, we constructed and validated two prognostic glutamine metabolic gene models, Clusters A and B, to better discriminate between groups of TNBC patients based on risk. Compared with the risk Cluster A patients, the Cluster B patients tended to exhibit better survival outcomes and higher immune cell infiltration. In addition, we established a scoring system, the glutamine metabolism score (GMS), to assess the pattern of glutamine metabolic modification. We found that solute carrier family 7 member 5 (SLC7A5), an amino acid transporter, was the most important gene and plays a vital role in glutamine metabolism reprogramming in TNBC cells. Knocking down SLC7A5 significantly inhibited human and mouse TNBC cell proliferation, migration, and invasion. In addition, downregulation of SLC7A5 increased CD8+ T-cell infiltration. The combination of a SLC7A5 blockade mediated via JPH203 treatment and an anti-programmed cell death 1 (PD-1) antibody synergistically increased the immune cell infiltration rate and inhibited tumor progression. Hence, our results highlight the molecular mechanisms underlying SLC7A5 effects and lead to a better understanding of the potential benefit of targeting glutamine metabolism in combination with immunotherapy as a new therapy for TNBC.

SOCS1 acts as a ferroptosis driver to inhibit the progression and chemotherapy resistance of triple-negative breast cancer.

Ferroptosis is involved in many types of cancers, including triple-negative breast cancer (TNBC). Suppressor of cytokine signaling 1 (SOCS1) has recently been implicated as a regulator of ferroptosis. We aim to explore whether targeting SOCS1 is a potential therapeutic strategy for TNBC therapy. Stable cell lines were constructed using lentivirus transfection. Cell viability was determined using CCK-8 and cell colony formation assays, respectively. Assays including lactate dehydrogenase release, lipid peroxidation and malondialdehyde assays were conducted to evaluate ferroptosis. Real-time quantitative polymerase chain reaction and western blotting were performed to evaluate mRNA and protein expression, respectively. A xenograft animal model was established by subcutaneous injection of cells into the flank. Our results showed that SOCS1 overexpression inhibited cell proliferation and induced ferroptosis in TNBC cells, while SOCS1 knockdown promoted cell proliferation and reduced ferroptosis. We also found that SOCS1 regulated ferroptosis by modulating GPX4 expression. Furthermore, SOCS1 regulated cisplatin resistance in TNBC cells by promoting ferroptosis. Our in vivo data suggested that SOCS1 regulated tumor growth and cisplatin resistance in vivo. SOCS1 inhibits the progression and chemotherapy resistance of TNBC by regulating GPX4 expression.

Inhibited Expression of NLRP12 Promotes the Development of Triple-Negative Breast Cancer by Activating the NF-κB Pathway

NLRP12 can affect the progression of different diseases, including hepatocellular carcinoma. However, no report on triple-negative breast cancer (TNBC) has been found. Thus, this study aimed to explore the role of NLRP12 in TNBC. In our study, immunohistochemistry, real-time quantitative PCR (qPCR), and Western blot assays were used to evaluate NLRP12 expression in TNBC tissues and cells. Then, NLRP12 lentivirus was constructed and infected into MDA-MB-231 and MDA-MB-157 cells with or without PTD-p65-P1 treatment. Next, cells were collected for cell function detection using the following procedures: colony formation assay for proliferation, Transwell for migration and invasion, and Western blot for NF-κB and MAPK pathway-associated proteins. Finally, a xenograft mouse model was applied; the tumor volume and weight were determined, and NLRP12, p-IκBb-α, and p-IκBb-α expressions were evaluated using qPCR and Western blot. Results indicated that NLRP12 was lowly expressed in TNBC tissues and cells. The inhibition of NLRP12 could induce the proliferation, migration, and invasion of TNBC cells, which also could be reversed by inhibiting the NF-κB pathway (PTD-p65-P1). Moreover, silencing of NLRP12 could upregulate p-IκBb-α, while IκBb-α, p-ERK, ERK, p-p38, p38, p-JNK, and JNK expressions remained unchanged, thereby indicating that only the NF-κB pathway could be activated by NLRP12 silencing. Furthermore, the xenograft mouse model confirmed the abovementioned findings. Therefore, the low expression of NLRP12 promoted the proliferation, migration, and invasion in TNBC cells by activating the NF-κB pathway. This study might provide insights into TNBC therapy.

SEPTIN3 Promotes Progression of Triple-Negative Breast Cancer via Activating Wnt Pathway.

There is a lack of targeted therapies for triple-negative breast cancer (TNBC), necessitating the search for novel targets. Patients with TNBC exhibit elevated expression of neuron-specific septin-3 (SEPTIN3), leading to poor prognosis. This study aimed to investigate the modulation of SEPTIN3 expression in TNBC cells. The relative expression levels of SEPTIN3 in TNBC tissues and cell lines were determined using Western blotting and qRT-PCR. We generated lentivirally transduced TNBC cell lines so such that SEPTIN3 was overexpressed or knocked down. Next, the effect of SEPTIN3 on the biological behavior of TNBC cells was detected using a series of functional assays, including CCK8, colony formation, scratch, and transwell assays. We monitored the tumorigenicity of SEPTIN3 overexpressed cells and performed Ki-67 immunostaining in mice. The mechanism mediated by SEPTIN3 was studied using functional enrichment analysis and Western blotting. Protein and mRNA expression levels of SEPTIN3 were observed to be increased in TNBC tissues and cell lines. SEPTIN3 knockdown reduced cell growth, invasion, and migration, whereas SEPTIN3 overexpression exerted the opposite effects. SEPTIN3 was observed to favor cell growth and tumorigenicity in vivo. In addition, SEPTIN3 promoted TNBC cell aggressiveness and proliferation via activation of the Wnt signaling pathway. SEPTIN3 emerged as an oncogene that accelerates tumor progression by regulating the Wnt signaling pathway.

Deubiquitinase USP19 modulates apoptotic calcium release and endoplasmic reticulum stress by deubiquitinating BAG6 in triple negative breast cancer.

Triple-negative breast cancer (TNBC), a heterogeneous subtype of breast cancer (BC), had poor prognosis. Endoplasmic reticulum (ER) stress was responsible for cellular processes and played a crucial role in the cell function. ER stress is a complex and dynamic process that can induce abnormal apoptosis and death. However, the underlying mechanism of ER stress involved in TNBC is not well defined. We identified ubiquitin-specific protease 19 (USP19) as a TNBC negative regulator for further investigation. The effects of USP19 on BC proliferation were assessed in vitro using proliferation test and cell-cycle assays, while the effects in vivo were examined using a mouse tumorigenicity model. Through in vitro flow cytometric analyses and in vivo TUNEL assays, cell apoptosis was assessed. Proteomics was used to examine the proteins that interact with USP19. Multiple in vitro and in vivo tests showed that USP19 decreases TNBC cell growth while increasing apoptosis. Then, we demonstrated that USP19 interacts with deubiquitinates and subsequently stabilises family molecular chaperone regulator 6 (BAG6). BAG6 can boost B-cell lymphoma 2 (BCL2) ubiquitination and degradation, thereby raising ER calcium (Ca2+ ) levels and causing ER stress. We also found that the N6 -methyladenosine (m6 A) "writer" methyltransferase-like 14 (METTL14) increased global m6 A modification. Our study reveals that USP19 elevates the intracellular Ca2+ concentration to alter ER stress via regulation of BAG6 and BCL2 stability and may be a viable therapeutic target for TNBC therapy.

ILT4 reprograms glucose metabolism to promote tumor progression in triple negative breast cancer.

Triple negative breast cancer (TNBC) is the most aggressive and poorly-treated subtype of breast cancer. Identifying novel drivers and mechanisms for tumor progression is quite essential for precise targeted therapy of TNBC. Immunoglobulin-like transcript (ILT) 4 is a classic myeloid suppressor for their activation and immune response. Our recent results found that ILT4 is also high expressed in lung cancer cells where has a role in promoting immune evasion and thus tumor formation. However, the expression and function of ILT4 in breast cancer remains elusive. Here, using our patient cohort and public database analysis, we found that TNBC displayed the most abundant ILT4 expression among all breast cancer subtypes. Functionally, enriched ILT4 promoted TNBC cell proliferation, migration and invasion in vitro, as well as tumor growth and metastasis in vivo. Further mechanistic analysis revealed that ILT4 reprogrammed aerobic glycolysis of tumor cells via AKT/mTOR signaling-mediated glucose transporter 3 (GLUT3) and Pyruvate kinase muscle 2 (PKM2) overexpression. ILT4 inhibition in TNBC reduced tumor progression and GLUT3/PKM2 expression in vivo. Our study identified a novel driver for TNBC progression and proposed a promising strategy to combat TNBC by targeting ILT4.

Association between event-free survival and overall survival in early-stage triple-negative breast cancer.

Aim: This study evaluated event-free survival (EFS) as a surrogate outcome for overall survival (OS) in neoadjuvant therapy for early-stage triple-negative breast cancer (eTNBC). Methods: Meta-regression analyses based on a targeted literature review were used to evaluate the individual- and trial-level associations between EFS and OS. Results: In the individual-level analyses, 3-year EFS was a significant predictor of 5-year OS (p<0.01; coefficient of determinations [R2]: 0.82 [95% CI: 0.68-0.91]). Additionally, there was a statistically significant association between the treatment effect on EFS and OS at the trial level (p<0.001; R2: 0.64 [95% CI: 0.45-0.82]). Conclusion: This study demonstrates significant associations between EFS and OS and suggests that EFS is a valid surrogate for OS following neoadjuvant therapy for eTNBC.

Advances in the Management of Early-Stage Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with both inter- and intratumor heterogeneity, thought to result in a more aggressive course and worse outcomes. Neoadjuvant therapy (NAT) has become the preferred treatment modality of early-stage TNBC as it allows for the downstaging of tumors in the breast and axilla, monitoring early treatment response, and most importantly, provides important prognostic information that is essential to determining post-surgical therapies to improve outcomes. It focuses on combinations of systemic drugs to optimize pathologic complete response (pCR). Excellent response to NAT has allowed surgical de-escalation in ideal candidates. Further, treatment algorithms guide the systemic management of patients based on their pCR status following surgery. The expanding knowledge of molecular pathways, genomic sequencing, and the immunological profile of TNBC has led to the use of immune checkpoint inhibitors and targeted agents, including PARP inhibitors, further revolutionizing the therapeutic landscape of this clinical entity. However, subgroups most likely to benefit from these novel approaches in TNBC remain elusive and are being extensively studied. In this review, we describe current practices and promising therapeutic options on the horizon for TNBC, surgical advances, and future trends in molecular determinants of response to therapy in early-stage TNBC.

CL4-modified exosomes deliver lncRNA DARS-AS1 siRNA to suppress triple-negative breast cancer progression and attenuate doxorubicin resistance by inhibiting autophagy

Triple-negative breast cancer (TNBC) is a fatal disease. Drug resistance and the lack of effective drugs are the leading causes of death in patients with TNBC. Recently, long non-coding RNAs have been proven to be effective drug design targets owing to their high tissue specificity; however, an effective drug delivery system is necessary for their clinical application. In this study, we constructed a novel nanodrug delivery system based on the epidermal growth factor receptor (EGFR)-targeted aptamer CL4-modified exosomes (EXOs-CL4) for the targeted delivery of aspartyl-tRNA synthetase-antisense RNA 1 (DARS-AS1) small interfering RNA (siRNA) and doxorubicin (DOX) to TNBC cells in vitro and in vivo. This delivery system exerted potent anti-proliferation, anti-migration, and pro-apoptotic effects on TNBC cells. Silencing DARS-AS1 increased the sensitivity of TNBC cells to DOX by suppressing the transforming growth factor-β (TGF-β)/Smad3 signaling pathway-induced autophagy, thereby enhancing the synergetic antitumor effects. Collectively, our findings revealed that EXOs-CL4-mediated delivery of DARS-AS1 siRNA can be used as a new treatment strategy for DOX-resistant TNBC. Moreover, EXOs-CL4 can be used as effective drug delivery systems for targeted TNBC therapy.

An Organofluorine Isoselenocyanate Analogue of Sulforaphane Affects Antimetabolite 5-Fluorouracil's Anticancer Activity: A Perspective for New Combinatory Therapy in Triple-Negative Breast Cancer.

Antimetabolites, especially 5-fluorouracil, are commonly used clinically to treat breast, colon, and other cancers. However, their side effects and inefficiency in monotherapy have prompted further searches for new combinations. Thus, the anticancer effect of 5-fluorouracil (5-FU) and the sulforaphane analogue, 4-isoselenocyanato-1-butyl 4'-fluorobenzyl sulfoxide (ISC), were tested in in vitro and in vivo models of triple-negative breast cancer (TNBC) as a new option for this treatment-resistant and aggressive type of breast cancer. A synergic interaction between 5-FU and ISC was observed in the TNBC in vitro model MDA-MB-231 cell line, which led to enhanced antiproliferative effects. The results of in vitro studies were confirmed by in vivo tests, which demonstrated stronger tumor growth inhibition and additive interactions between 5-FU and ISC in the murine TNBC model. Moreover, the results of the body mass and blood analysis showed the safety of the tested combination. The mechanistic study revealed that the combined treatment triggered apoptosis and necrosis, as well as inhibited cell migration.

Challenges and Opportunities in Developing Targeted Therapies for Triple Negative Breast Cancer.

Triple negative breast cancer (TNBC) is a heterogeneous group of breast cancers characterized by their lack of estrogen receptors, progesterone receptors, and the HER2 receptor. They are more aggressive than other breast cancer subtypes, with a higher mean tumor size, higher tumor grade, the worst five-year overall survival, and the highest rates of recurrence and metastasis. Developing targeted therapies for TNBC has been a major challenge due to its heterogeneity, and its treatment still largely relies on surgery, radiation therapy, and chemotherapy. In this review article, we review the efforts in developing targeted therapies for TNBC, discuss insights gained from these efforts, and highlight potential opportunities going forward. Accumulating evidence supports TNBCs as multi-driver cancers, in which multiple oncogenic drivers promote cell proliferation and survival. In such multi-driver cancers, targeted therapies would require drug combinations that simultaneously block multiple oncogenic drivers. A strategy designed to generate mechanism-based combination targeted therapies for TNBC is discussed.

Fasting-mimicking diet: a metabolic approach for the treatment of breast cancer.

Metabolic reprogramming is a new and potentially targetable hallmark of cancer. In recent years, fasting and fasting-mimicking diets (FMDs) have been tested as anticancer strategies both in preclinical experiments and in clinical trials. In this review, we aim at summarizing the available evidence about the antitumour activity of these approaches in preclinical breast cancer models, as well as results from clinical trials investigating fasting/FMD in breast cancer patients. Preclinical evidence demonstrated that nutrient deprivation boosts the antitumor activity of chemotherapy, immunotherapy or targeted therapies in triple-negative breast cancer (TNBC) and HR+/HER2 models through both cell-autonomous antitumour effects in cancer cells and favourable modifications in intratumor immune cells. Several clinical experiences demonstrated that fasting/FMD is feasible and well tolerated in combination with standard treatments in BC patients, and that it could reduce chemotherapy-related toxicities. Finally, despite the absence of randomized trials demonstrating the antitumor activity of fasting/FMD in breast cancer patients, preliminary clinical reports suggest that this experimental nutritional strategy may enhance chemotherapy activity. Randomized clinical trials are ongoing to validate these results at a larger scale. Fasting/FMD is a promising therapeutic approach in patients with breast cancer; ongoing and future trials will confirm their role in improving breast cancer care.

Automated quantification of stromal tumour infiltrating lymphocytes is associated with prognosis in breast cancer.

Stromal tumour infiltrating lymphocytes (sTIL) in haematoxylin and eosin (H&E) stained sections has been linked to better outcomes and better responses to neoadjuvant therapy in triple-negative and HER2-positive breast cancer (TNBC and HER2 +). However, the infiltrate includes different cell populations that have specific roles in the tumour immune microenvironment. Various studies have found high concordance between sTIL visual quantification and computational assessment, but specific data on the individual prognostic impact of plasma cells or lymphocytes within sTIL on patient prognosis is still unknown. In this study, we validated a deep-learning breast cancer sTIL scoring model (smsTIL) based on the segmentation of tumour cells, benign ductal cells, lymphocytes, plasma cells, necrosis, and 'other' cells in whole slide images (WSI). Focusing on HER2 + and TNBC patient samples, we assessed the concordance between sTIL visual scoring and the smsTIL in 130 WSI. Furthermore, we analysed 175 WSI to correlate smsTIL with clinical data and patient outcomes. We found a high correlation between sTIL values scored visually and semi-automatically (R = 0.76; P = 2.2e-16). Patients with higher smsTIL had better overall survival (OS) in TNBC (P = 0.0021). In the TNBC cohort, smsTIL was as an independent prognostic factor for OS. As part of this work, we introduce a new segmentation dataset of H&E-stained WSI.

Antiproliferation and apoptosis studies of estrone pharmacophores in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that shows high metastatic capability and poor prognosis. The aggressive behavior of TNBC may involve amplified EGFR expression. Currently, no targeted therapy has been approved for treating TNBC, which urgently needs novel treatment options. In this study, we report that estrone analogs with novel pharmacophores exhibited high potency toward TNBC cells through multiple mechanisms, inhibition of cell proliferation via EGFR receptor, and induction of mitochondrial apoptosis. Molecular docking studies revealed that hit analogs MMA307 and MMA321 were potent against the EGFR receptor (pdb code: 1M17) in silico and were over 10-fold more potent than sorafenib (positive control) when dosed against MDA-MB-468 cells in vitro. MMA307 and MMA321 induced mitochondrial apoptosis as characterized by condensed nuclei with fragmented chromatin, phosphatidylserine flip and modulated expressions of Apaf1, cytochrome c, and caspases 3 and 9. MMA307 and MMA321 inhibited TNBC proliferation through suppression of EGFR and activated EGFR (Y1068) expressions. Similarly, EGFR signaling pathways, RAF/ERK and AKT/mTOR, were inhibited as pARaf, pERK1/2 (characterizes RAF/ERK pathway) and pAKT, pmTOR, p70S6Kα (characterizes AKT/mTOR pathway) were all suppressed. Moreover, MMA307 and MMA321 inhibited TNBC cell growth through downregulation of cyclin D1 expression and arresting TNBC cells in the G1 phase of cell cycle. This study reports for the first time that estrone congeners with novel pharmacophores may be an effective therapy for TNBC. Findings from this research provide a solid foundation for further preclinical and clinical studies in developing estrone derivatives as novel TNBC therapeutics.

Predicting pathological complete response to neoadjuvant systemic therapy for triple-negative breast cancers using deep learning on multiparametric MRIs.

We trained and validated a deep learning model that can predict the treatment response to neoadjuvant systemic therapy (NAST) for patients with triple negative breast cancer (TNBC). Dynamic contrast enhanced (DCE) MRI and diffusion-weighted imaging (DWI) of the pre-treatment (baseline) and after four cycles (C4) of doxorubicin/cyclophosphamide treatment were used as inputs to the model for prediction of pathologic complete response (pCR). Based on the standard pCR definition that includes disease status in either breast or axilla, the model achieved areas under the receiver operating characteristic curves (AUCs) of 0.96 ± 0.05, 0.78 ± 0.09, 0.88 ± 0.02, and 0.76 ± 0.03, for the training, validation, testing, and prospective testing groups, respectively. For the pCR status of breast only, the retrained model achieved prediction AUCs of 0.97 ± 0.04, 0.82 ± 0.10, 0.86 ± 0.03, and 0.83 ± 0.02, for the training, validation, testing, and prospective testing groups, respectively. Thus, the developed deep learning model is highly promising for predicting the treatment response to NAST of TNBC.Clinical Relevance- Deep learning based on serial and multiparametric MRIs can potentially distinguish TNBC patients with pCR from non-pCR at the early stage of neoadjuvant systemic therapy, potentially enabling more personalized treatment of TNBC patients.

Targeting Mcl-1 by a small molecule NSC260594 for triple-negative breast cancer therapy

Triple-negative breast cancers (TNBCs) are aggressive forms of breast cancer and tend to grow and spread more quickly than most other types of breast cancer. TNBCs can neither be targeted by hormonal therapies nor the antibody trastuzumab that targets the HER2 protein. There are urgent unmet medical needs to develop targeted drugs for TNBCs. We identified a small molecule NSC260594 from the NCI diversity set IV compound library. NSC260594 exhibited dramatic cytotoxicity in multiple TNBCs in a dose-and time-dependent manner. NSC260594 inhibited the Myeloid cell leukemia-1 (Mcl-1) expression through downregulation of Wnt signaling proteins. Consistent with this, NSC260594 treatment increased apoptosis, which was confirmed by using an Annexin-V/PI assay. Interestingly, NSC260594 treatment reduced the cancer stem cell (CSC) population in TNBCs. To make NSC260594 more clinically relevant, we treated NSC260594 with TNBC cell derived xenograft (CDX) mouse model, and with patient-derived xenograft (PDX) organoids. NSC260594 significantly suppressed MDA-MB-231 tumor growth in vivo, and furthermore, the combination treatment of NSC260594 and everolimus acted synergistically to decrease growth of TNBC PDX organoids. Together, we found that NSC260594 might serve as a lead compound for triple-negative breast cancer therapy through targeting Mcl-1.

Natural compound So-2 suppresses triple-negative breast cancer through inducing ferroptosis via downregulating transcription factor E2F7

Triple-negative breast cancer (TNBC), accounting for about 15∼18% of all breast cancers, is notorious for its poor prognosis, high rate of relapse and short overall survival. Because of lacking effective therapeutic targets or drugs, treatment of TNBC in clinical encounters great obstacle. Siegesbeckiaorientalis L. have been used as a traditional Chinese medicine “Xi-Xian-Cao” for centuries with multiple medicinal benefits including cancerous treatment. We have reported the isolation of twenty-seven germacranolides including So-2 from the aerial parts of S. orientalis with potent cytotoxicity against breast cancer cells. The studyaims to verified the anti-TNBC function of the natural compound So-2 both in vitro and vivo and uncover the underlying mechanism. The results showed that So-2 caused cell cycle arrest and suppress TNBC cell proliferation and migration. Also, So-2 was first identified to be a bona fide ferroptosis inducer in TNBC cells. So-2 effectively suppressed tumor growth of TNBC by using an orthotopic transplantation tumor model. We also characterized the oncogenic role of the transcription factor E2F7 in TNBC. E2F7 was demonstrated to be involved in the ferroptosis-inducing and tumor suppression effect of So-2. Altogether, So-2 exhibits inhibitory effect on TNBC both in vitro and vivo by inducing TNBC ferroptosis via downregulating the expression of E2F7. These findings provide valuable insight into the pathogenesis of TNBC. The natural compound So-2, isolated from Chinese traditional medicine, might be a prospective drug candidate in TNBC therapy.

Codelivery of Que and BCL-2 siRNA with Lipid-Copolymer Hybrid Nanocomplexes for Efficient Tumor Regression.

The efficacy of chemotherapy is often reduced due to the chemotherapy resistance of tumor cells, which is usually caused by abnormal gene overexpression. Herein, multifunctional nanocomplexes (Que/siBCL2@BioMICs) were developed to deliver quercetin (Que) and BCL-2 siRNA (siBCL2) to synergistically inhibit tumor growth. The nanocomplexes were composed of an amphiphilic triblock copolymer of poly(ethylene glycol) methyl ether methacrylate-poly[2-(dimethylamino) ethyl acrylate]-polycaprolactone (PEGMA-PDMAEA-PCL) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol)-biotin (DSPE-PEG-biotin). Que was encapsulated into the cores through hydrophobic interactions, while negatively charged siBCL2 was loaded through electrostatic interactions. The nanocomplexes could effectively facilitate cellular uptake via biotin-mediated active targeting and cytosolic release of cargos by the "proton sponge effect" of PDMAEA. Que/siBCL2@BioMICs achieved enhanced cytotoxicity and anti-metastasis activity due to a synergistic effect of Que and siBCL2 in vitro. More importantly, superior anti-tumor efficacy was observed in orthotopic 4T1 tumor-bearing mice with reduced primary tumor burden and lung metastatic nodules, while no obvious side effects to major organs were observed. In conclusion, the biotin-targeted nanocomplexes with chemotherapeutic and nucleotide agent entrapment provide a promising strategy for efficient triple-negative breast cancer (TNBC) therapy.

Tumor targeting and therapeutic assessments of RNA nanoparticles carrying α9-nAChR aptamer and anti-miR-21 in triple-negative breast cancers

Triple-negative breast cancer (TNBC) is highly aggressive with a poor prognosis because of a lack of cell markers as drug targets. α9-Nicotinic acetylcholine receptor (nAChR) is expressed abundantly in TNBC; thus, it is a valuable biomarker for TNBC detection and treatment. In this study, we utilized thermodynamically stable three-way junction (3WJ) packaging RNA (pRNA) as the core to construct RNA nanoparticles with an α9-nAChR RNA aptamer as a targeting ligand and an anti-microRNA-21 (miR-21) as a therapeutic module. We compared the configuration of the two RNA nanoparticles and found that 3WJ-B-α9-nAChR-aptamer fluorescent RNA nanoparticles (3WJ-B-α9-apt-Alexa) exhibited better specificity for α9-nAChR in TNBC cells compared with 3WJ-C-α9-nAChR. Furthermore, 3WJ-B-α9-apt-Alexa bound more efficiently to TNBC patient-derived xenograft (PDX) tumors than 3WJ fluorescent RNA nanoparticles (3WJ-Alexa) with little or no accumulation in healthy organs after systemic injection in mice. Moreover, 3WJ-B-α9-nAChR-aptamer RNA nanoparticles carrying anti-miR-21 (3WJ-B-α9-apt-anti-miR-21) significantly suppressed TNBC-PDX tumor growth and induced cell apoptosis because of reduced miR-21 gene expression and upregulated the phosphatase and tensin homolog (PTEN) and programmed cell death 4 (PDCD4) proteins. In addition, no pathological changes were detected upon toxicity examination of treated mice. In conclusion, the 3WJ-B-α9-nAChR-aptamer RNA nanoparticles established in this study efficiently deliver therapeutic anti-miR-21, indicating their potential as a novel TNBC therapy.

Co-Delivery of Hesperetin and Cisplatin via Hyaluronic Acid-Modified Liposome for Targeted Inhibition of Aggression and Metastasis of Triple-Negative Breast Cancer.

Having no specific therapy for triple-negative breast cancer (TNBC), this subtype has the lowest survival rate and highest metastatic risk of breast cancer since the tumor inflammatory microenvironment mainly accounts for heterogeneity-induced insensitivity to chemotherapy and epithelial-mesenchymal transition (EMT). This study reports hyaluronic acid (HA)-modified liposomes loaded with cisplatin (CDDP) and hesperetin (Hes) (CDDP-HA-Lip/Hes) for active targeting to relieve systematic toxicity and effective anti-tumor/anti-metastasis ability of TNBC. Our results revealed that HA modification promoted the cellular uptake of the synthesized CDDP-HA-Lip/Hes nanoparticles in MDA-MB-231 cells and accumulation in tumor sites in vivo, indicating deeper tumor penetration. Importantly, CDDP-HA-Lip/Hes inhibited the PI3K/Akt/mTOR pathway to alleviate the inflammation in the tumor and with a crosstalk to suppress the process of the EMT, increasing the chemosensitivity and inhibiting tumor metastasis. Meanwhile, CDDP-HA-Lip/Hes could significantly inhibit the aggression and metastasis of TNBC with less side effects on normal tissues. Overall, this study provides a tumor-targeting drug delivery system with great potential for treating TNBC and its lung metastasis robustly.