Breast Cancer Metastasis Suppressor Research Articles

Bio-inspired Oxidative Stress Amplifier for Suppressing Cancer Metastasis and Imaging-Guided Combination Therapy

Antioxidant-defense systems of tumor cells protect them from oxidative damage and is strongly associated with tumor metastasis. In this work, a mussel-inspired multifunctional nanomedicine (ZS-MB@P) has been designed for inhibiting tumor growth and metastasis through amplified oxidative stress and photothermal/magnetothermal/photodynamic triple-combination therapy. This nanomedicine was fabricated via loading a silica shell on the magnetic nano-octahedrons [zinc-doped magnetic Fe3O4 nano-octahedrons] by encapsulating photosensitizer methylene blue (MB) and subsequently coating polydopamine (PDA) shells as "gatekeeper." The nanomedicine could realize photothermal therapy, photodynamic therapy, and magnetic hyperthermia after treatment with near-infrared (NIR) irradiation and applied magnetic field. Under pH and NIR stimulation, controlled amount of MB was released to produced exogenous reactive oxygen species. Noteworthy, PDA can amplify intracellular oxidative stress by depleting glutathione, thus inhibiting breast cancer metastasis effectively since oxidative stress is an important barrier to tumor metastasis. The outstanding ability to suppress tumor growth and metastasis was comprehensively assessed and validated both in vitro and in vivo. Moreover, the nanomedicine showed outstanding T2 magnetic resonance imaging for tracking the treatment process. Taken together, this work offers an innovative approach in the synergistic treatment of recalcitrant breast cancer.

Pirfenidone suppressed triple-negative breast cancer metastasis by inhibiting the activity of the TGF-β/SMAD pathway.

Among breast cancer patients, metastases are the leading cause of death. Despite decades of effort, little progress has been made to improve the treatment of breast cancer metastases, especially triple-negative breast cancer (TNBC). The extracellular matrix plays an important role in tumour growth and metastasis by causing its deposition, remodelling, and signalling. As we know, the process of fibrosis results in excessive amounts of extracellular matrix being deposited within the cells. So, it will be interesting to study if the use of anti-fibrotic drugs in combination with conventional chemotherapy drugs can produce synergistic antitumor effects. In this study, we assessed the efficacy of Pirfenidone (PFD), an FDA-approved medication for the treatment of idiopathic pulmonary fibrosis, on TNBC cells as well as its anti-tumour effects in xenograft tumour model. PFD inhibited in a dose-dependent manner breast cancer cell proliferation, migration, and invasion, while promoted their apoptosis in vitro. PFD also suppressed TGF-β-induced activation of Smad signalling pathway and expression level of EMT-inducing transcription factors (e.g. SNAI2, TWIST1, ZEB1) as well as the mesenchymal genes such as VIMENTIN and N-Cadherin. On the contrary, the expression level of epithelial marker gene E-Cadherin was up-regulated in the presence of PFD. In vivo, PFD alone exerted a milder but significant anti-tumour effect than the chemotherapy drug nanoparticle albumin-bound paclitaxel (nab-PTX) did in the breast cancer xenograft mouse model. Interestingly, PFD synergistically boosted the cancer-killing effect of nab-PTX. Furthermore, Our data suggest that PFD suppressed breast cancer metastasis by inhibiting the activity of the TGFβ/SMAD pathway.

Intermittent F-actin Perturbations by Magnetic Fields Inhibit Breast Cancer Metastasis.

F-actin (filamentous actin) has been shown to be sensitive to mechanical stimuli and play critical roles in cell attachment, migration, and cancer metastasis, but there are very limited ways to perturb F-actin dynamics with low cell toxicity. Magnetic field is a noninvasive and reversible physical tool that can easily penetrate cells and human bodies. Here, we show that 0.1/0.4-T 4.2-Hz moderate-intensity low-frequency rotating magnetic field-induced electric field could directly decrease F-actin formation in vitro and in vivo, which results in decreased breast cancer cell migration, invasion, and attachment. Moreover, low-frequency rotating magnetic fields generated significantly different effects on F-actin in breast cancer vs. noncancerous cells, including F-actin number and their recovery after magnetic field retrieval. Using an intermittent treatment modality, low-frequency rotating magnetic fields could significantly reduce mouse breast cancer metastasis, prolong mouse survival by 31.5 to 46.0% (P < 0.0001), and improve their overall physical condition. Therefore, our work demonstrates that low-frequency rotating magnetic fields not only can be used as a research tool to perturb F-actin but also can inhibit breast cancer metastasis through F-actin modulation while having minimum effects on normal cells, which reveals their potential to be developed as temporal-controlled, noninvasive, and high-penetration physical treatments for metastatic cancer.

A nanotherapeutic approach to selectively eliminate metastatic breast cancer cells by targeting cell surface GRP78.

Here, rational engineering of doxorubicin prodrug loaded peptide-targeted liposomal nanoparticles to selectively target metastatic breast cancer cells in vivo is described. Glucose-regulated protein 78 (GRP78), a heat shock protein typically localized in the endoplasmic reticulum in healthy cells, has been identified to home to the cell surface in certain cancers, and thus has emerged as a promising therapeutic target. Recent reports indicated GRP78 to be expressed on the cell surface of an aggressive subpopulation of stem-like breast cancer cells that exhibit metastatic potential. In this study, a targeted nanoparticle formulation with a GRP78-binding peptide (Kd of 7.4 ± 1.0 μM) was optimized to selectively target this subpopulation. In vitro studies with breast cancer cell lines showed the targeted nanoparticle formulation (TNPGRP78pep) achieved enhanced cellular uptake, while maintaining selectivity over the control groups. In vivo, TNPGRP78pep loaded with doxorubicin prodrug was evaluated using a lung metastatic mouse model and demonstrated inhibition of breast cancer cell seeding to lungs down at the level of negative control groups. Combined, this study established that specific-targeting of surface GRP78 expressing a subpopulation of aggressive breast cancer cells was able to inhibit breast cancer metastasis to lungs, and underpinned the significance of GRP78 in breast cancer metastasis.

Cell Metabolomics Reveals the Potential Mechanism of Aloe Emodin and Emodin Inhibiting Breast Cancer Metastasis.

Metastasis is one of the main obstacles for the treatment and prognosis of breast cancer. In this study, the effects and possible mechanisms of aloe emodin (AE) and emodin (EMD) for inhibiting breast cancer metastasis were investigated via cell metabolomics. First, a co-culture model of MCF-7 and HUVEC cells was established and compared with a traditional single culture of MCF-7 cells. The results showed that HUVEC cells could promote the development of cancer cells to a malignant phenotype. Moreover, AE and EMD could inhibit adhesion, invasion, and angiogenesis and induce anoikis of MCF-7 cells in co-culture model. Then, the potential mechanisms behind AE and EMD inhibition of MCF-7 cell metastasis were explored using a metabolomics method based on UPLC-Q-TOF/MS multivariate statistical analysis. Consequently, 27 and 13 biomarkers were identified in AE and EMD groups, respectively, including polyamine metabolism, methionine cycle, TCA cycle, glutathione metabolism, purine metabolism, and aspartate synthesis. The typical metabolites were quantitatively analyzed, and the results showed that the inhibitory effect of AE was significantly better than EMD. All results confirmed that AE and EMD could inhibit metastasis of breast cancer cells through different pathways. Our study provides an overall view of the underlying mechanisms of AE and EMD against breast cancer metastasis.

Distinct expression and function of breast cancer metastasis suppressor 1 in mutant P53 glioblastoma.

Glioblastoma (GBM) is the most malignant subtype of astrocytic tumors with the worst prognosis in all its progressive forms. Breast cancer metastasis suppressor 1 (BRMS1) is a metastasis suppressor gene that controls malignancy in multiple tumors. As yet, however, its clinical and functional significance in mutant P53 GBM remains inconclusive. Here, we attempted to study the importance of BRMS1 in mutant P53 GBM. BRMS1 expression was evaluated in 74 human astrocytoma tissues by qRT-PCR, Western blotting and immunohistochemistry. BRMS1 expression in the astrocytoma tissues was correlated with clinicopathological parameters, the P53 mutation status and BRMS1 downstream targets, and compared with TCGA and NCI-60 datasets. siRNA-mediated knockdown of BRMS1 was performed in selected GBM cell lines to evaluate the functional role of BRMS1. Our study revealed an enhanced expression of BRMS1 in GBM which was associated with a poor patient survival, and this observation was corroborated by the TCGA dataset. We also found a positive correlation between BRMS1 expression and a mutant P53 status in GBM which was associated with a poor prognosis. In vitro BRMS1 silencing reduced the growth of mutant P53 GBM cells and repressed their colonization and migration/invasion by modulating EGFR-AKT/NF-κB signaling. Transcriptional profiling revealed a positive and negative correlation of uPA and ING4 expression with BRMS1 expression, respectively. Our data indicate upregulation of BRMS1 in high grade astrocytomas which correlates positively with mutant P53 and a poor patient survival. Silencing of BRMS1 in mutant P53 GBM cell lines resulted in a reduced cellular growth and migration/invasion by suppressing the EGFR-AKT/NF-kB signaling pathway. BRMS1 may serve as a predictive biomarker and therapeutic target in mutant P53 GBM.

Retraction Note to: Inhibition of breast cancer metastasis with microRNA-302a by downregulation of CXCR4 expression

Retraction Note to: Inhibition of breast cancer metastasis with microRNA-302a by downregulation of CXCR4 expression

Alkaloid Derivative (Z)-3β-Ethylamino-Pregn-17(20)-en Inhibits Triple-Negative Breast Cancer Metastasis and Angiogenesis by Targeting HSP90α.

Metastasis is an important cause of cancer-related death. Previous studies in our laboratory found that pregnane alkaloids from Pachysandra terminalis had antimetastatic activity against breast cancer cells. In the current study, we demonstrated that treatment with one of the alkaloid derivatives, (Z)-3β-ethylamino-pregn-17(20)-en (1), led to the downregulation of the HIF-1α/VEGF/VEGFR2 pathway, suppressed the phosphorylation of downstream molecules Akt, mTOR, FAK, and inhibited breast cancer metastasis and angiogenesis both in vitro and in vivo. Furthermore, the antimetastasis and antiangiogenesis effects of 1 treatment (40 mg/kg) were more effective than that of Sorafenib (50 mg/kg). Surface plasmon resonance (SPR) analysis was performed and the result suggested that HSP90α was a direct target of 1. Taken together, our results suggested that compound 1 might represent a candidate antitumor agent for metastatic breast cancer.

An Application of Tumor-Associated Macrophages as Immunotherapy Targets: Sialic Acid-Modified EPI-Loaded Liposomes Inhibit Breast Cancer Metastasis.

Breast cancer metastasis is an important cause of death in patients with breast cancer and is closely related to circulating tumor cells (CTCs) and the metastatic microenvironment. As the most infiltrating immune cells in the tumor microenvironment (TME), tumor-associated macrophages (TAMs), which highly express sialic acid (SA) receptor (Siglec-1), are closely linked to tumor progression and metastasis. Furthermore, the surface of CTCs also highly expressed receptor (Selectin) for SA. A targeting ligand (SA-CH), composed of SA and cholesterol, was synthesized and modified on the surface of epirubicin (EPI)-loaded liposomes (EPI-SL) as an effective targeting delivery system. Liposomes were evaluated for characteristics, stability, in vitro release, cytotoxicity, cellular uptake, pharmacokinetics, tumor targeting, and pharmacodynamics. In vivo and in vitro experiments showed that EPI-SL enhanced EPI uptake by TAMs. In addition, cellular experiments showed that EPI-SL could also enhance the uptake of EPI by 4T1 cells, resulting in cytotoxicity second only to that of EPI solution. Pharmacodynamic experiments have shown that EPI-SL has optimal tumor inhibition with minimal toxicity, which can be ascribed to the fact that EPI-SL can deliver drugs to tumor based on TAMs and regulate TME through the depletion of TAMs. Our study demonstrated the significant potential of SA-modified liposomes in antitumor metastasis. Schematic diagram of the role of SA-CH modified EPI-loaded liposomes in the model of breast cancer metastasis.

Anti-metastatic function of triterpene phytochemicals from guggul by targeting tumor-intrinsic NF-kB activation in triple-negative breast cancer cells

BackgroundThe endogenous activity of NF-κB is often elevated in various types of cancer cells, particularly breast cancer, and is strongly correlated with the induction of target genes that can inhibit apoptosis, interact with cell-cycle regulation, promote cell invasion and contribute to tumorigenesis, inflammation, and metastatic growth as well as drug resistance. Thus, the downregulation of NF-κB is regarded as a promising therapeutic target to inhibit breast cancer growth and metastasis. PurposeSince no NF-κB inhibitor has yet been approved by the FDA, we aim to identify small molecules from natural resources that could potentially inhibit NF-κB and suppress breast cancer metastasis. Study designIn the current study, nineteen extracts from different valuable medicinal plants were screened for their prospective biological activity against NF-κB transcriptional activation in 4T1 breast cancer cells, followed by isolation and purification analysis of the major active compounds from guggul extract, as it exhibited the most inhibitory efficacy of NF-κB activation. ResultsA bioassay-guided isolation of active constituents from the promising candidate, guggul methanol extract (GU-M), using NF-κB reporter gene assay was performed to identify potential anti-metastatic agents for triple-negative breast cancer cells (TNBC) and resulted in the isolation of four known major compounds namely; guggulsterone M (1), guggulsterol Ι (2), myyrhanol A (3), and myyrhanone A (4). ConclusionAmong the isolated compounds, myrrhanol A and myrrhanone A at the concentration of 10 μM markedly inhibited the intrinsic NF-κB pathway and potently suppressed the proliferative and metastatic abilities of murine and human breast cancer cells; 4T1, MDA-MB-231, and MDA-MB-453.

Immunoglobulin superfamily 9 (IGSF9) is trans-activated by p53, inhibits breast cancer metastasis via FAK

Metastasis of breast cancer represents the major reason for its poor prognosis, leading to high mortality. In breast cancer, a tumor suppressor gene TP53 is commonly mutated. TP53 mutation leads to an altered expression of various genes, an event that is associated with aggressive tumor and is a strong independent marker for survival. In this study, we identified a novel p53 target gene, immunoglobulin superfamily 9 (IGSF9). IGSF9 is generally down-regulated in breast cancer tissues. Loss of IGSF9 is associated with frequent metastasis and poor prognosis of breast cancer patients. Wild-type p53, but not R175H mutant, trans-activates the transcription of IGSF9 via binding to its promoter (−137 to −131 bp), inhibits epithelial-mesenchymal transition (EMT), consequently the inhibition of breast cancer cells migration and invasion. IGSF9 interacts with focal adhesion kinase (FAK) and inhibits FAK/AKT signaling activity. PND1186, FAK inhibitor, inhibits breast cancer metastasis induced by IGSF9 knockdown in vitro and in vivo. Taken together, IGSF9 is trans-activated by p53 and inhibits breast cancer metastasis by modulating FAK/AKT signaling pathway. IGSF9 could serve as a prognostic marker and potential therapeutic target for breast cancer.

Nuclear import of PTPN18 inhibits breast cancer metastasis mediated by MVP and importin β2

Distant metastasis is the primary cause of breast cancer-associated death. The existing information, such as the precise molecular mechanisms and effective therapeutic strategies targeting metastasis, is insufficient to combat breast cancer. This study demonstrates that the protein tyrosine phosphatase PTPN18 is downregulated in metastatic breast cancer tissues and is associated with better metastasis-free survival. Ectopic expression of PTPN18 inhibits breast cancer cell metastasis. PTPN18 is translocated from the cytoplasm to the nucleus by MVP and importin β2 in breast cancer. Then, nuclear PTPN18 dephosphorylates ETS1 and promotes its degradation. Moreover, nuclear PTPN18 but not cytoplasmic PTPN18 suppresses transforming growth factor-β signaling and epithelial-to-mesenchymal transition by targeting ETS1. Our data highlight PTPN18 as a suppressor of breast cancer metastasis and provide an effective antimetastatic therapeutic strategy.

Diltiazem inhibits breast cancer metastasis via mediating growth differentiation factor 15 and epithelial-mesenchymal transition

Migration and metastasis commonly happen to triple-negative breast cancer (TNBC) patients with advanced diseases. In many studies, it has been suggested that epithelial-mesenchymal transition (EMT) is one of the key mechanisms triggering cancer metastasis. Accumulating evidence has proven that calcium channel blockers mediate cell motility. Therefore, we attempt to investigate the effects of diltiazem, which has been selected from several FDA-approved clinical calcium channel blockers, on EMT in TNBC. By using both mouse and human TNBC cell lines, we found that diltiazem decreases colony formation and cell migration in breast cancer cells. The expression of epithelial markers such as E-cadherin and ZO-1 were increased dose-dependently by diltiazem, while mesenchymal markers such as Snail and Twist were decreased. In addition, we found that the expression of growth differentiation factor-15 (GDF-15) was also increased by diltiazem. Administering recombinant GDF-15 also reverses EMT, inhibits colony formation and migration in breast cancer cells. Moreover, treatment with diltiazem in tumor-bearing mice also decreases cancer metastasis and nodule formation, with more GDF-15 expression in diltiazem-treated mice than saline-treated mice, respectively. These findings suggest that diltiazem regulates EMT and cell motility through elevating GDF-15 expression in breast cancers in vitro and in vivo.

Dual-miRNA-Propelled Three-Dimensional DNA Walker for Highly Specific and Rapid Discrimination of Breast Cancer Cell Subtypes in Clinical Tissue Samples

Dual-miRNA-Propelled Three-Dimensional DNA Walker for Highly Specific and Rapid Discrimination of Breast Cancer Cell Subtypes in Clinical Tissue Samples

ICAM-1 on Breast Cancer Cells Suppresses Lung Metastasis but Is Dispensable for Tumor Growth and Killing by Cytotoxic T Cells.

Breast tumors and their derived circulating cancer cells express the leukocyte β2 integrin ligand Intercellular adhesion molecule 1 (ICAM-1). We found that elevated ICAM-1 expression in breast cancer cells results in a favorable outcome and prolonged survival of breast cancer patients. We therefore assessed the direct in vivo contribution of ICAM-1 expressed by breast cancer cells to breast tumorigenesis and lung metastasis in syngeneic immunocompetent mice hosts using spontaneous and experimental models of the lung metastasis of the C57BL/6-derived E0771 cell line, a luminal B breast cancer subtype. Notably, the presence of ICAM-1 on E0771 did not alter tumor growth or the leukocyte composition in the tumor microenvironment. Interestingly, the elimination of Tregs led to the rapid killing of primary tumor cells independently of tumor ICAM-1 expression. The in vivo elimination of a primary E0771 tumor expressing the ovalbumin (OVA) model neoantigen by the OVA-specific OVA-tcr-I mice (OT-I) transgenic cytotoxic T lymphocytes (CTLs) also took place normally in the absence of ICAM-1 expression by E0771 breast cancer target cells. The whole lung imaging of these cells by light sheet microscopy (LSM) revealed that both Wild type (WT)- and ICAM-1-deficient E0771 cells were equally disseminated from resected tumors and accumulated inside the lung vasculature at similar magnitudes. ICAM-1-deficient breast cancer cells developed, however, much larger metastatic lesions than their control counterparts. Strikingly, the vast majority of these cells gave rise to intravascular tumor colonies both in spontaneous and experimental metastasis models. In the latter model, ICAM-1 expressing E0771- but not their ICAM-1-deficient counterparts were highly susceptible to elimination by neutrophils adoptively transferred from E0771 tumor-bearing donor mice. Ex vivo, neutrophils derived from tumor-bearing mice also killed cultured E0771 cells via ICAM-1-dependent interactions. Collectively, our results are a first indication that ICAM-1 expressed by metastatic breast cancer cells that expand inside the lung vasculature is involved in innate rather than in adaptive cancer cell killing. This is also a first indication that the breast tumor expression of ICAM-1 is not required for CTL-mediated killing but can function as a suppressor of intravascular breast cancer metastasis to lungs.

Abstract 6261A: Chinese medicinal herbs Scutellaria barbata and Oldenlandia diffusa modulate apoptosis via induction of pro-apoptotic and anti-apoptotic proteins in MDA-MB-157 and 93B breast cancer cells

Abstract Scutellaria barbata (SB) and Oldenlandia diffusa (OD) have been used in Traditional Chinese Medicine for treating colon cancer, glioblastoma, and ovarian cancer liver, lung, and rectal cancers. These two herbs are included in most of the herbal cancer treatment formulas in China and Taiwan hospitals. We previously demonstrated that aqueous extracts of SB and OD inhibited mutagenesis, DNA binding, and metabolism of aflatoxin B1 and benzo[a]pyrene in carcinogenesis. In studies by Hugo (2006) and Perez (2010), the efficacy of BZL 101 (an extract of SB) has been demonstrated in preliminary Phase Ia and Ib clinical trials in metastatic breast cancer patients. It is also shown to induce an S phase arrest of the cell cycle by affecting the Cycline A2 and CDK2 expression in estrogen-sensitive MCF7 and estrogen insensitive MDA-MB-231 breast cancer cells. MeOH and BuOH extract of OD have been illustrated to reduce MCF7 invasion via the inhibition of MMP-9 and ICAM-1 apoptotic proteins expression. Ursolic acid of OD could inhibit breast cancer metastasis by suppressing glycolytic metabolism through activating SP1/Caveolin-1 signaling. In this study, the effectiveness of aqueous extract of SB and OD in the modulation of apoptosis of breast cancer cell lines MDA-MB-157 and 93B (a drug-resistant APC-mutant of it) were investigated. Assessments were performed using green/red/blue fluorescent Apoptosis/Necrosis Detection Test and the Human Apoptosis Antibody Array - Membrane [43 Targets] Test (Abcam). Our fluorescent apoptosis data showed that 3-hours treatment with 2.5 mg aqueous extract of SB induced a statistically significant percentage of apoptosis in MDA-MB-157 (46.5 ± 7.5% &amp;gt; 16%± 1.0%, p &amp;lt; 0.05) and 93B (46.5 ± 7.5% &amp;gt; 16%± 1.0%, p &amp;lt; 0.05) as compared to the negative control. Similar results were obtained with the OD treatment. From the antibody array-membrane experiments, modulation of various apoptosis markers by SB such as the pro-apoptotic proteins BID and BIM (p=0.019; p=0.007) in MDA-MB-157 and Bad (p=0.002), Bax (p=0.020), BID (p=0.001), p27 (p=0.004), p53 (p=0.022) in 93B as compared to the negative controls; and anti-apoptotic markers BcL-2, FasL, IGF-I, and p21 were also observed. OD treatment also induced similar significant production of these two types of proteins. These results suggest that SB and OD contain phytochemicals that induce apoptosis in MDA-MB-157 and 93B via the modulation of these pro-apoptotic and anti-apoptotic proteins. Citation Format: MinSeo Kang, Nathaly Manrique, Rekha Issac, Sarah Wolf, Jasmine Cha, SungBeen Han, Hugo Jie Qin, Lun Kim, Padma P. Uppala, Brian Yuen Yau Wong. Chinese medicinal herbs Scutellaria barbata and Oldenlandia diffusa modulate apoptosis via induction of pro-apoptotic and anti-apoptotic proteins in MDA-MB-157 and 93B breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6261A.

MiR-3614-3p suppresses cell aggressiveness of human breast cancer by targeting AKT3 and HDAC1 expression.

BackgroundMicroRNAs (miRNAs) regulate various pathophysiological functions and pathobiological progression in various cancers. Our recent study reported that miR-3614-3p significantly suppressed the proliferation of breast cancer (BC) cells by downregulating its host gene TRIM25. However, other functional roles of miR-3614-3p migration and invasion in BC and its potential mechanisms are not clearly elucidated.MethodsIn this study, we investigated miR-3614-3p regulation of AKT3 and HDAC1 expression in BC. miR-3614-3p and AKT3/HDAC1 mRNA expression levels were determined using quantitative real-time PCR (qRT-PCR) in MCF-7 and MDA-MB-231 BC cells. The effects of miR-3614-3p on migration and invasion were measured using wound healing and transwell migration assays. In BC cells, miR-3614-3p levels were remarkably low, and AKT3 and HDAC1 mRNA and protein levels were high as assessed by qRT-PCR and western blot. Finally, we investigated the role of AKT3/HDAC1 using silent interfering RNA (siRNA) and confirmed the targeting of AKT3 and HDAC1 3' UTR through miR-3614-3p using a luciferase reporter assay.ResultsIn the present study, we found that overexpression of miR-3614-3p markedly suppressed tumor cell invasion and migration independent of TRIM25, whereas other target genes, AKT3 and HDAC1, were involved. Moreover, we found that the resulting silencing of AKT3 and HDAC1 suppressed cell migration.ConclusionsmiR-3614-3p is an anti-oncogene that can suppress BC cells by targeting AKT3 and HDAC1, revealing the potential role of miR-3614-3p in suppressing BC metastasis. Therefore, miR-3614 may act as a potential biomarker for BC prognosis.

Copper-based theranostic nanocatalysts for synergetic photothermal-chemodynamic therapy

Chemodynamic therapy (CDT) has aroused extensive attention as a potent therapeutic modality. However, its practical application is severely restricted by the strong acidity requirement for Fenton reaction and upregulated antioxidant defense within metastatic breast cancer. Herein, a copper-based single-site nanocatalyst functionalized with carbonic anhydrase inhibitor (CAI) was constructed for magnetic resonance/photoacoustic imaging (MRI/PA)-guided synergetic photothermal therapy (PTT) and CDT. Once reaching tumor sites, the nanocatalyst can be recognized by tumor cell membranes-overexpressed carbonic anhydrase IX (CA IX). Subsequently, the single-site CuII can be reduced to CuI by the tumor-overexpressed glutathione (GSH), which simultaneously impaired the tumor antioxidant defense system and triggered CAI release for inducing intracellular H+ accumulation. Further, the decreased intracellular pH can accelerate the nanocatalyst biodegradation to release more CuII and CAI to participate in next-cycle GSH-depletion and cytoplasm acidification, respectively, thereby continuously supplying CuI and H+ for self-cyclically amplified CDT. Upon laser irradiation, the nanocatalyst can generate local heat, which not only permits PTT but also enhances the nanocatalyst-mediated CDT. Moreover, the suppression of CA IX can hinder the tumor extracellular matrix degradation to prevent tumor metastasis. Overall, this work highlighted the great application prospect in enhancing CDT via tumor acidic/redox microenvironment remodeling, and provides an insightful paradigm for inhibiting breast cancer metastasis. STATEMENT OF SIGNIFICANCE: The practical application of chemodynamic therapy (CDT) is severely restricted by the strong acidity requirement for Fenton reaction and upregulated antioxidant defense within cancer. Herein, we developed a carbonic anhydrase inhibitor (CAI)-functionalized Cu-based nanocatalyst. Once reaching tumor sites, the CuII can be reduced to CuI by the tumor-overexpressed glutathione (GSH), which simultaneously impaired the tumor antioxidant system and triggered CAI release for inducing intracellular H+ accumulation. Further, the decreased intracellular pH can accelerate the nanocatalyst biodegradation to release more CuII and CAI to participate in next-cycle GSH-depletion and cytoplasm acidification, respectively, thus continuously supplying CuI and H+ for self-cyclically amplified CDT. Upon laser irradiation, the nanocatalyst not only permits PTT but also enhances the CDT.

NSrp70 suppresses metastasis in triple-negative breast cancer by modulating Numb/TβR1/EMT axis.

Alternative splicing of mRNA precursors allows cancer cells to create different protein isoforms that promote growth and survival. Compared to normal cells, cancer cells frequently exhibit a higher diversity of their transcriptomes. A comprehensive understanding of splicing regulation is required to correct the splicing alterations for the future precision oncology. A quantitative proteomic screen was performed to identify the regulators associated the metastasis in triple-negative breast cancer. Multiple in vitro and in vivo functional analyses were used to study the effects of NSrp70 on breast cancer metastasis. Next, transcriptomic sequencing (RNA-seq) and alternative splicing bioinformatics analysis was applied to screen the potential targets of NSrp70. Moreover, in vitro splicing assays, RNA pull-down, and RNA immunoprecipitation assay were used to confirm the specific binding between NSrp70 and downstream target genes. Furthermore, the prognostic value of NSrp70 was analyzed in a cohort of patients by performing IHC. We uncovered NSrp70 as a novel suppressor of breast cancer metastasis. We discovered that NSrp70 inhibited the skipped exon alternative splicing of NUMB, promoted the degradation of transforming growth factor receptor 1 through lysosome pathway, and regulated TGFβ/SMAD-mediated epithelial-mesenchymal transition phenotype in breast cancer cells. Furthermore, high NSrp70 expression correlated with a better prognosis in breast cancer patients. Our findings revealed that splicing regulator NSrp70 serves as a metastasis suppressor.

Hypoxia-Responsive Stereocomplex Polymeric Micelles with Improved Drug Loading Inhibit Breast Cancer Metastasis in an Orthotopic Murine Model.

Tumor metastasis is a leading cause of breast cancer-related death. Taxane-loaded polymeric formulations, such as Genexol PM and Nanoxel M using poly(ethylene glycol)-poly(d,l-lactide) (PEG-PLA) micelles as drug carriers, have been approved for the treatment of metastatic breast cancer. Unfortunately, the physical instability of PEG-PLA micelles, leading to poor drug loading, premature drug leakage, and consequently limited drug delivery to tumors, largely hinders their therapeutic outcome. Inspired by the enantiomeric nature of PLA, this work developed stereocomplex PEG-PLA micelles through stereoselective interactions of enantiomeric PLA, which are further incorporated with a hypoxia-responsive moiety used as a hypoxia-cleavable linker of PEG and PLA, to maximize therapeutic outcomes. The results showed that the obtained micelles had high structural stability, showing improved drug loading for effective drug delivery to tumors as well as other tissues. Especially, they were capable of sensitively responding to the hypoxic tumor environment for drug release, reversing hypoxia-induced drug resistance and hypoxia-promoted cell migration for enhanced bioavailability under hypoxia. In vivo results further showed that the micelles, especially at a high dose, inhibited the growth of the primary tumor and improved tumor pathological conditions, consequently remarkably inhibiting its metastasis to the lungs and liver, while not causing any systemic toxicity. Hypoxia-responsive stereocomplex micelles thus emerge as a reliable drug delivery system to treat breast cancer metastasis.