RESUMO
It has been discovered that Trichorhinophalangeal Syndrome-1 (TRPS1), a novel member of the GATA transcription factor family, participates in both normal physiological processes and the development of numerous diseases. Recently, TRPS1 has been identified as a new biomarker to aid in cancer diagnosis and is very common in breast cancer (BC), especially in triple-negative breast cancer (TNBC). In this review, we discussed the structure and function of TRPS1 in various normal cells, focused on its role in tumorigenesis and tumor development, and summarize the research status of TRPS1 in the occurrence and development of BC. We also analyzed the potential use of TRPS1 in guiding clinically personalized precision treatment and the development of targeted drugs.
Assuntos
Biomarcadores Tumorais , Neoplasias da Mama , Proteínas de Ligação a DNA , Proteínas Repressoras , Fatores de Transcrição , Humanos , Feminino , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Regulação Neoplásica da Expressão Gênica , Carcinogênese/genética , Carcinogênese/metabolismo , AnimaisRESUMO
BACKGROUND: Although progress has been made in accurate diagnosis and targeted treatments, breast cancer (BC) patients with metastasis still present a grim prognosis. With the continuous emergence and development of new personalized and precision medicine targeting specific tumor biomarkers, there is an urgent need to find new metastatic and prognostic biomarkers for BC patients. METHODS: We were dedicated to identifying genes linked to metastasis and prognosis in breast cancer through a combination of in silico analysis and experimental validation. RESULTS: A total of 25 overlap differentially expressed genes were identified. Ten hub genes (namely MRPL13, CTR9, TCEB1, RPLP0, TIMM8B, METTL1, GOLT1B, PLK2, PARL and MANBA) were identified and confirmed. MRPL13, TCEB1 and GOLT1B were shown to be associated with the worse overall survival (OS) and were optionally chosen for further verification by western blot. Only MRPL13 was found associated with cell invasion, and the expression of MRPL13 in metastatic BC was significantly higher than in primary BC. CONCLUSION: We proposed MRPL13 could be a potential novel biomarker for the metastasis and prognosis of breast cancer.
Assuntos
Biomarcadores Tumorais , Neoplasias da Mama , Simulação por Computador , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Feminino , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Prognóstico , Regulação Neoplásica da Expressão Gênica , Metástase Neoplásica , Perfilação da Expressão Gênica/métodos , Linhagem Celular Tumoral , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: In highly aggressive malignant cancers including breast cancer, vasculogenic mimicry (VM) is the potential of tumor cells to generate a vascular channel network for delivering blood to tumor cells. Detection of genes involved in this process is critical to designing targeted therapy against breast cancer metastasis. In this study, we evaluated the roles of FAK and ILK in the progression of VM in metastatic breast tumor cells. RESULTS: Primary (4T1T), and highly metastatic (4T1B and 4T1L) breast tumor cells were isolated from cancerous mice. The potential of cancer cells to organize themselves into vascular-like structures (VM) has been evaluated with in vitro assessment. The expression of ILK and FAK were examined using real-time polymerase chain reaction. We confirmed the high ability of metastatic tumor cells in vascular-like structure formation. In molecular analysis, our data showed that ILK and FAK expression was significantly elevated in metastatic breast tumor cells. These results indicated that the higher potential of metastatic tumor cells in vascular-like structure formation may be related to higher expression of ILK and FAK. Analysis of molecular features of metastatic tumor cells could be utilized to create a targeted therapeutic strategy against metastasis in breast cancer.
Assuntos
Neoplasias da Mama , Metástase Neoplásica , Proteínas Serina-Treonina Quinases , Transdução de Sinais , Animais , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Feminino , Camundongos , Linhagem Celular Tumoral , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/metabolismo , Neovascularização Patológica/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Camundongos Endogâmicos BALB C , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Quinase 1 de Adesão Focal/metabolismo , Quinase 1 de Adesão Focal/genética , Regulação Neoplásica da Expressão GênicaRESUMO
Typhonium flagelliforme (T. flagelliforme) is an Indonesian rodent tuber plant traditionally used to treat cancer diseases. Although gamma-ray irradiation has been used to increase the content in the chemical compounds of the T. flagelliforme plants with anticancer activity ten times effective, the specific effect of the isolated compounds from the mutant plants has never been reported yet. The potential cytotoxic agents were characterized via nuclear magnetic resonance spectroscopy, infrared spectroscopy, and mass spectrometry as stigmasterol and 7α-hydroxyl stigmasterol; and their anticancer activity was investigated. The in silico biochemical profile of the two compounds were analyzed by molecular docking and molecular dynamics simulation to confirm its interaction with the agonist binding site of Farsenoid X receptor (FXR). Stigmasterol and 7α-hydroxyl stigmasterol can act as a competitive regulator with a high-affinity for the FXR. The results also showed that stigmasterol and 7α-hydroxyl stigmasterol were the most potential and active fraction of the T. flagelliforme mutant plant against the MCF-7 human breast cancer cell line, with IC 50 value 9.13 µM and 12.97 µM, compared with cisplastin as a control about 13.20 µM. These results demonstrate the potential of stigmasterol and 7α-hydroxyl stigmasterol in T. flagelliforme mutant plants to act towards cancer diseases.
Assuntos
Simulação de Acoplamento Molecular , Humanos , Células MCF-7 , Estigmasterol/farmacologia , Estigmasterol/isolamento & purificação , Tubérculos/química , Antineoplásicos Fitogênicos/farmacologia , Simulação por Computador , Animais , Mutação , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Simulação de Dinâmica Molecular , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismoRESUMO
Recent advances in cancer research have highlighted the pivotal role of tertiary lymphoid structures (TLSs) in modulating immune responses, particularly in breast cancer (BRCA). Here, we performed an integrated analysis of bulk transcriptome data from over 6000 BRCA samples using biological network-based computational strategies and machine learning (ML) methods, and identified LGALS2 as a key marker within TLSs. Single-cell sequencing and spatial transcriptomics uncover the role of LGALS2 in TLS-associated dendritic cells (DCs) stimulation and reveal the complexity of the tumor microenvironment (TME) at both the macro and micro levels. Elevated LGALS2 expression correlates with prolonged survival, which is associated with a robust immune response marked by diverse immune cell infiltration and active anti-tumor pathways leading to a 'hot' tumor microenvironment. The colocalization of LGALS2 with TLS-associated DCs and its role in immune activation in BRCA were confirmed by hematoxylin-eosin (HE), immunohistochemistry (IHC), and in vivo validation analyses. The identification of LGALS2 as a key factor in BRCA not only highlights its therapeutic potential in novel TLS-directed immunotherapy but also opens new avenues in patient stratification and treatment selection, ultimately improving clinical management.
Assuntos
Neoplasias da Mama , Células Dendríticas , Galectina 2 , Imunoterapia , Estruturas Linfoides Terciárias , Microambiente Tumoral , Humanos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/genética , Feminino , Microambiente Tumoral/imunologia , Imunoterapia/métodos , Estruturas Linfoides Terciárias/imunologia , Estruturas Linfoides Terciárias/patologia , Galectina 2/genética , Galectina 2/metabolismo , Animais , Biomarcadores Tumorais , Regulação Neoplásica da Expressão Gênica , Camundongos , Análise de Célula Única , PrognósticoRESUMO
Increased MMP-9 expression in the tumor microenvironment (TME) plays a crucial role in the extracellular matrix remodeling to facilitate cancer invasion and metastasis. However, the mechanism of MMP-9 upregulation in TME remains elusive. Since TGF-ß and TNF-α levels are elevated in TME, we asked whether these two agents interacted to induce/augment MMP-9 expression. Using a well-established MDA-MB-231 breast cancer model, we found that the synergy between TGF-ß and TNF-α led to MMP-9 upregulation at the transcriptional and translational levels, compared to treatments with each agent alone. Our in vitro findings are corroborated by co-expression of elevated MMP-9 with TGF-ß and TNF-α in human breast cancer tissues. Mechanistically, we found that the MMP-9 upregulation driven by TGF-ß/TNF-α cooperativity was attenuated by selective inhibition of the TGF-ßRI/Smad3 pathway. Comparable outcomes were observed upon inhibition of TGF-ß-induced phosphorylation of Smad2/3 and p38. As expected, the cells defective in Smad2/3 or p38-mediated signaling did not exhibit this synergistic induction of MMP-9. Importantly, the inhibition of histone methylation but not acetylation dampened the synergistic MMP-9 expression. Histone modification profiling further identified the H3K36me2 as an epigenetic regulatory mark of this synergy. Moreover, TGF-ß/TNF-α co-stimulation led to increased levels of the transcriptionally permissive dimethylation mark at H3K36 in the MMP-9 promoter. Comparable outcomes were noted in cells deficient in NSD2 histone methyltransferase. In conclusion, our findings support a cooperativity model in which TGF-ß could amplify the TNF-α-mediated MMP-9 production via chromatin remodeling and facilitate breast cancer invasion and metastasis.
Assuntos
Neoplasias da Mama , Regulação Neoplásica da Expressão Gênica , Metaloproteinase 9 da Matriz , Metástase Neoplásica , Fator de Crescimento Transformador beta , Fator de Necrose Tumoral alfa , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/genética , Fator de Necrose Tumoral alfa/metabolismo , Feminino , Fator de Crescimento Transformador beta/metabolismo , Linhagem Celular Tumoral , Histonas/metabolismo , Metilação , Transdução de Sinais , Microambiente TumoralRESUMO
Background: The proteome is a crucial reservoir of targets for cancer treatment. While some targeted therapies have been developed, there are still significant challenges in early diagnosis and treatment, highlighting the need to identify new biomarkers and therapeutic targets for breast cancer. Therefore, we conducted a comprehensive proteome-wide Mendelian randomization (MR) study to identify novel biomarkers and potential therapeutic targets for breast cancer. Methods: Protein quantitative trait locus (pQTL) data were extracted from two published plasma proteome-wide association studies. Genetic variants associated with breast cancer were obtained from the Breast Cancer Association Consortium, which included 133,384 cases and 113,789 controls, and the Finnish cohort study, comprising 18,786 cases and 182,927 controls. We employed summary-based MR and colocalization methods to identify potential drug targets for breast cancer, which were subsequently validated using a two-sample MR approach. Finally, a protein-protein interaction (PPI) network was constructed to detect interactions between the identified proteins and existing cancer drug targets. Results: Gene-predicted levels of ten proteins were associated with breast cancer risk. Decreased levels of CASP8, DDX58, CPNE1, ULK3, PARK7, and BTN2A1, as well as increased levels of TNFRSF9, TNXB, DNPH1, and TLR1, were linked to an elevated risk of breast cancer. Among these, CASP8 and DDX58 were supported by tier-one evidence, while CPNE1, ULK3, PARK7, and TNFRSF9 received tier-two evidence support. The remaining proteins, TNXB, BTN2A1, DNPH1, and TLR1, were supported by tier-three evidence. CASP8, DDX58, CPNE1, ULK3, PARK7, and TNFRSF9 have already been identified as targets in drug development and potential therapeutic targets for breast cancer treatment. Additionally, ULK3 showed promise as a prognostic biomarker for breast cancer. Conclusions: The present study identified several novel potential drug targets and biomarkers for breast cancer, providing new insights into its diagnosis and treatment. The integration of PPI and druggability evaluations enhances the prioritization of these therapeutic targets, paving the way for future drug development efforts.
Assuntos
Biomarcadores Tumorais , Neoplasias da Mama , Análise da Randomização Mendeliana , Proteômica , Locos de Características Quantitativas , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/sangue , Neoplasias da Mama/metabolismo , Feminino , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/metabolismo , Proteômica/métodos , Proteoma/metabolismo , Mapas de Interação de Proteínas , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo ÚnicoAssuntos
Neoplasias da Mama , Regulação Neoplásica da Expressão Gênica , MicroRNAs , Receptor ErbB-2 , Receptor IGF Tipo 1 , Humanos , MicroRNAs/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Feminino , Receptor IGF Tipo 1/metabolismo , Receptor IGF Tipo 1/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Progressão da Doença , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genéticaRESUMO
Hypoxia occurs in 90% of solid tumors and is strongly associated with an increased propensity for metastasis. Hypoxia induces tumor progression largely through inducing HIF-mediated transcription, resulting in alterations to tumor cell metabolism, as well as increases in migration and invasion. Hypoxia also results in a myriad of changes to the tumor microenvironment (TME). While many studies have examined the immediate effects of hypoxia on tumor cells and the associated TME, far fewer have focused on the long-term consequences of transient reductions in oxygen. In this issue of Cancer Research, Iriondo and colleagues examined whether short-term exposure to hypoxia leads to a "hypoxic memory" in the context of breast cancer. The authors used established cell lines and circulating tumor cell lines to demonstrate that these cells harbor a hypoxic memory that sustains downregulation of IFN signaling and antigen presentation (AP) pathways that contribute to tumor progression via alterations to tumor cells and the TME. The authors further showed that cells that have experienced hypoxia maintain the reduction in IFN signaling in vivo and are more aggressive. They determined that the hypoxic memory and reduction of IFN signaling can be reversed with a histone deacetylase inhibitor, entinostat, providing a potential means to reverse hypoxia-induced suppression of IFN signaling. As suppression of IFN signaling has the potential to influence both tumor cells and the TME, the identification of a strategy to inhibit long-term suppression of IFN signaling downstream of hypoxia could prove to be an effective means to target tumor progression. See related article by Iriondo et al., p. 3141.
Assuntos
Neoplasias da Mama , Progressão da Doença , Transdução de Sinais , Humanos , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/genética , Feminino , Microambiente Tumoral , Interferons/metabolismo , Oxigênio/metabolismo , Hipóxia Celular , Animais , Linhagem Celular TumoralRESUMO
Breast cancer is the most common type of cancer among women. The molecular subtypes of breast cancer, depending on the Estrogen Receptor (ER), Progesterone Receptor (PR) and Human Epidermal Growth Factor Receptor (HER-2) status, usually play a vital role for the adjuvant treatment. Interestingly, there is a good possibility of change of receptor status in the recurrence of same primary tumor. The study is designed April 2018 to March 2019 to see the concordance in triple-receptor expression (ER, PR, and HER-2) between the primary and the locally recurrent breast cancer patient and the results can be able to influence the management and prognosis of the breast cancer patients. This observational study was carried out in the department of surgical oncology, NICRH where total 48 patients were studied who were subjected to core biopsy of recurrent lesion for ER, PR and HER-2 status. A structured case record form was used to interview and collect data. Data analysis was done using SPSS version 26.0 to see concordance and discordance in triple-receptor expression between the primary and the locally recurrent breast cancer patient. Among 48 cases, 12(25.0%), 10(20.83%) and 2(4.16%) patients showed Estrogen Receptor (ER), Progesterone Receptor (PR) and Human Epidermal Growth Factor Receptor (Her-2) discordance that are statistically significant in every receptor status. Majority discordance of ER, PR and Her-2 were associated with invasive duct cell carcinoma (IDC); ER & Her-2 discordance was equally associated with histological grade 2 and 3 whereas PR discordance had significant association with grade 3. Staging of disease showed that all ER, PR and Her-2 discordance were associated with stage (p<0.05). Besides, majority discordance was mostly associated with lumpectomy except Her-2 discordance. Besides, among the adjuvant treatment regimen chemotherapy along with radiotherapy was mostly associated with discordance of all receptors (p<0.05). Estrogen Receptor (ER), Progesterone Receptor (PR) and Human Epidermal Growth Factor Receptor (HER-2) status of primary breast cancer showed 25.0%, 20.83% and 4.16% discordant in recurrent episodes in this study. Invasive duct cell carcinoma, histological grade 2 and 3, stage II, stage III, MRM and CT along with RT are major attributable factors in this study.
Assuntos
Neoplasias da Mama , Recidiva Local de Neoplasia , Receptor ErbB-2 , Receptores de Estrogênio , Receptores de Progesterona , Humanos , Feminino , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , Receptores de Progesterona/metabolismo , Pessoa de Meia-Idade , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Adulto , Quimioterapia Adjuvante , IdosoRESUMO
Lepidagathis cristata (L. cristata) plant produces reducing and capping agents; this study utilized microwave-assisted biogenic synthesis to manufacture silver nanoparticles (AgNPs) using this plant. The structure, morphology, and crystallinity phases of prepared nanoparticles (NPs) were characterized by ultraviolet-visible spectroscopy (UV-viz), powder X-ray diffraction (XRD), Fourier-transform infrared (FTIR) spectroscopy, and scanning electron microscopy (SEM). Biologically synthesized AgNPs were treated against pathogenic bacteria species including Escherichia coli (E. coli), Bacillus subtilis (B. subtilis), and Staphylococcus aureus (S. aureus) and its highest zone of inhibition 10 ± 1.45 mm, 10 ± 0.74 mm, and 6 ± 0.43 mm, respectively, at the concentration of 100 µg/mL. The cytotoxic activity of AgNPs against MCF-7 breast cancer cells revealed significant growth inhibition by inhibiting cell viability, inhibitory concentration of 50% (IC50) of NPs observed at 55.76 µg/mL concentration. Finally, our findings concluded that the L. cristata-mediated biosynthesized AgNPs proved its potential antibacterial and neoplastic properties against MCF cells by endorsing the inhibition of cell proliferation especially with low concentration.
Assuntos
Antibacterianos , Ensaios de Seleção de Medicamentos Antitumorais , Nanopartículas Metálicas , Testes de Sensibilidade Microbiana , Extratos Vegetais , Prata , Prata/química , Prata/farmacologia , Nanopartículas Metálicas/química , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Humanos , Células MCF-7 , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Bacillus subtilis/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/síntese química , Água/química , Relação Dose-Resposta a Droga , FemininoRESUMO
BACKGROUND: Breast cancer metastasis remains the leading cause of cancer-related deaths in women worldwide. Infiltration of tumor-associated macrophages (TAMs) in the tumor stroma is known to be correlated with reduced overall survival. The inhibitors of TAMs are sought after for reprogramming the tumor microenvironment. Signal transducer and activator of transcription 3 (STAT3) is well known to contribute in pro-tumoral properties of TAMs. 2-Methoxyestradiol (2ME2), a potent anticancer and antiangiogenic agent, has been in clinical trials for treatment of breast cancer. Here, we investigated the potential of 2ME2 in modulating the pro-tumoral effects of TAMs in breast cancer. METHODS: THP-1-derived macrophages were polarized to macrophages with or without 2ME2. The effect of 2ME2 on macrophage surface markers and anti-inflammatory genes was determined by Western blotting, flow cytometry, immunofluorescence, qRTâPCR. The concentration of cytokines secreted by cells was monitored by ELISA. The effect of M2 macrophages on malignant properties of breast cancer cells was determined using colony formation, wound healing, transwell, and gelatin zymography assays. An orthotopic model of breast cancer was used to determine the effect of 2ME2 on macrophage polarization and metastasis in vivo. RESULTS: First, our study found that polarization of monocytes to alternatively activated M2 macrophages is associated with the reorganization of the microtubule cytoskeleton. At lower concentrations, 2ME2 treatment depolymerized microtubules and reduced the expression of CD206 and CD163, suggesting that it inhibits the polarization of macrophages to M2 phenotype. However, the M1 polarization was not significantly affected at these concentrations. Importantly, 2ME2 inhibited the expression of several anti-inflammatory cytokines and growth factors, including CCL18, TGF-ß, IL-10, FNT, arginase, CXCL12, MMP9, and VEGF-A, and hindered the metastasis-promoting effects of M2 macrophages. Concurrently, 2ME2 treatment reduced the expression of CD163 in tumors and inhibited lung metastasis in the orthotopic breast cancer model. Mechanistically, 2ME2 treatment reduced the phosphorylation and nuclear translocation of STAT3, an effect which was abrogated by colivelin. CONCLUSIONS: Our study presents novel findings on mechanism of 2ME2 from the perspective of its effects on the polarization of the TAMs via the STAT3 signaling in breast cancer. Altogether, the data supports further clinical investigation of 2ME2 and its derivatives as therapeutic agents to modulate the tumor microenvironment and immune response in breast carcinoma.
Assuntos
2-Metoxiestradiol , Neoplasias da Mama , Fator de Transcrição STAT3 , Macrófagos Associados a Tumor , 2-Metoxiestradiol/farmacologia , Humanos , Feminino , Fator de Transcrição STAT3/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Camundongos , Animais , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/imunologia , Microambiente Tumoral/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/imunologia , Linhagem Celular Tumoral , Ativação de Macrófagos/efeitos dos fármacos , Células THP-1 , Ensaios Antitumorais Modelo de Xenoenxerto , Citocinas/metabolismoRESUMO
BACKGROUND: Breast cancer is the second leading cause of death in women, with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) as the two most common forms of invasive breast cancer. While estrogen receptor positive (ER+) IDC and ILC are treated similarly, the multifocality of ILC presents challenges in detection and treatment, worsening long-term clinical outcomes in patients. With increasing documentation of chemoresistance in ILC, additional treatment options are needed. Oncolytic adenoviral therapy may be a promising option, but cancer cells must express the coxsackievirus & adenovirus receptor (CAR) for adenoviral therapy to be effective. The present study aims to evaluate the extent to which CAR expression is observed in ILC in comparison to IDC, and how the levels of CAR expression correlate with adenovirus transduction efficiency. The effect of liposome encapsulation on transduction efficiency is also assessed. METHODS: To characterize CAR expression in invasive breast carcinoma, 36 formalin-fixed paraffin-embedded (FFPE) human breast tumor samples were assayed by CAR immunohistochemistry (IHC). Localization of CAR in comparison to other junctional proteins was performed using a multiplex immunofluorescence panel consisting of CAR, p120-catenin, and E-cadherin. ILC and IDC primary tumors and cell lines were transduced with E1- and E3-deleted adenovirus type 5 inserted with a GFP transgene (Ad-GFP) and DOTAP liposome encapsulated Ad-GFP (DfAd-GFP) at various multiplicities of infection (MOIs). Transduction efficiency was measured using a fluorescence plate reader. CAR expression in the human primary breast carcinomas and cell lines was also evaluated by IHC. RESULTS: We observed membranous CAR, p120-catenin and E-cadherin expression in IDC. In ILC, we observed cytoplasmic expression of CAR and p120-catenin, with absent E-cadherin. Adenovirus effectively transduced high-CAR IDC cell lines, at MOIs as low as 12.5. Ad-GFP showed similar transduction as DfAd-GFP in high-CAR IDC cell lines. Conversely, Ad-GFP transduction of ILC cell lines was observed only at MOIs of 50 and 100. Furthermore, Ad-GFP did not transduce CAR-negative IDC cell lines even at MOIs greater than 100. Liposome encapsulation (DfAd-GFP) improved transduction efficiency 4-fold in ILC and 17-fold in CAR-negative IDC cell lines. CONCLUSION: The present study demonstrates that oncolytic adenoviral therapy is less effective in ILC than IDC due to differences in spatial CAR expression. Liposome-enhanced delivery may be beneficial for patients with ILC and tumors with low or negative CAR expression to improve adenoviral therapeutic effectiveness.
Assuntos
Adenoviridae , Neoplasias da Mama , Proteína de Membrana Semelhante a Receptor de Coxsackie e Adenovirus , Transdução Genética , Humanos , Feminino , Neoplasias da Mama/terapia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Adenoviridae/genética , Proteína de Membrana Semelhante a Receptor de Coxsackie e Adenovirus/metabolismo , Proteína de Membrana Semelhante a Receptor de Coxsackie e Adenovirus/genética , Linhagem Celular Tumoral , Carcinoma Lobular/metabolismo , Carcinoma Lobular/terapia , Carcinoma Lobular/genética , Carcinoma Lobular/patologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/terapia , Caderinas/metabolismo , Caderinas/genética , Vetores Genéticos/genética , Vetores Genéticos/administração & dosagem , LipossomosRESUMO
OBJECTIVE: To investigate the relationship between the expression of androgen receptor (AR) and clinical characteristics in breast cancer. PATIENTS AND METHODS: The clinical records of all 432 patients tested for AR in our institution between January 2020 and May 2023 were reviewed. Clinical characteristics, age, menopausal status, tumor node metastasis (TNM) stage, distant metastasis, pathological complete response (pCR), histopathological features histological grade, estrogen receptor (ER), progesterone receptor, Her-2, Ki-67, and molecular subtype were registered for all patients. RESULTS: About 377 (87.27%) of the 432 patients had AR expression. No significant difference in AR expression was found with age, menopausal status, TNM stage of primary tumor, or pCR. AR was positively and significantly associated with the histological grade, and recurrence. The AR expression was significantly related with molecular subtypes, including ER, PR Her-2, Ki67 and molecular subtype. ER (OR = 10.489, 95%CI: 5.470-21.569), PR (OR = 7.690, 95%CI: 3.974-16.129, Her-2 (OR = 10.489, 95%CI: 2.779-23.490 and tumor recurrence (OR = 0.110, 95%CI: 0.031-0.377 were significant independent risk factors affecting AR expression. CONCLUSIONS: AR expression can serve as a reliable basis for judging the clinical molecular types and poor prognosis for breast cancer. AR may be a novel biomarker and target in AR-positive breast cancer depending on significant difference in AR expression among different molecular types of breast cancer.
Assuntos
Biomarcadores Tumorais , Neoplasias da Mama , Recidiva Local de Neoplasia , Receptor ErbB-2 , Receptores Androgênicos , Receptores de Estrogênio , Receptores de Progesterona , Humanos , Receptores Androgênicos/metabolismo , Feminino , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Pessoa de Meia-Idade , Biomarcadores Tumorais/metabolismo , Prognóstico , Adulto , Receptores de Progesterona/metabolismo , Receptor ErbB-2/metabolismo , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Receptores de Estrogênio/metabolismo , Seguimentos , Idoso , Estudos Retrospectivos , Metástase Linfática , Estadiamento de Neoplasias , Gradação de Tumores , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: Although tumor cells undergoing epithelial-mesenchymal transition (EMT) typically exhibit spindle morphology in experimental models, such histomorphological evidence of EMT has predominantly been observed in rare primary spindle carcinomas. The characteristics and transcriptional regulators of spontaneous EMT in genetically unperturbed non-spindled carcinomas remain underexplored. METHODS: We used primary culture combined with RNA sequencing (RNA-seq), single-cell RNA-seq (scRNA-seq), and in situ RNA-seq to explore the characteristics and transcription factors (TFs) associated with potential spontaneous EMT in non-spindled breast carcinoma. RESULTS: Our primary culture revealed carcinoma cells expressing diverse epithelial-mesenchymal traits, consistent with epithelial-mesenchymal plasticity. Importantly, carcinoma cells undergoing spontaneous EMT did not necessarily exhibit spindle morphology, even when undergoing complete EMT. EMT was a favored process, whereas mesenchymal-epithelial transition appeared to be crucial for secondary tumor growth. Through scRNA-seq, we identified TFs that were sequentially and significantly upregulated as carcinoma cells progressed through the EMT process, which correlated with increasing VIM expression. Once upregulated, the TFs remained active throughout the EMT process. ZEB1 was a key initiator and sustainer of EMT, as indicated by its earliest significant upregulation in the EMT process, its exact correlation with VIM expression, and the reversal of EMT and downregulation of EMT-upregulated TFs upon ZEB1 knockdown. The correlation between ZEB1 and vimentin expression in triple-negative breast cancer and metaplastic breast carcinoma tumor cohorts further highlighted its role. The immediate upregulation of ZEB2 following that of ZEB1, along with the observation that the knockdown of ZEB1 or ZEB2 downregulates both ZEB1 and ZEB2 concomitant with the reversal of EMT, suggests their functional cooperation in EMT. This finding, together with that of a lack of correlation of SNAI1, SNAI2, and TWIST1 expression with the mesenchymal phenotype, indicated EMT-TFs have a context-dependent role in EMT. Upregulation of EMT-related gene signatures during EMT correlated with poor patient outcomes, highlighting the biological importance of the model. Elevated EMT gene signatures and increased ZEB1 and ZEB2 expression in vimentin-positive compared to vimentin-negative carcinoma cells within the corresponding primary tumor tissue confirmed ZEB1 and ZEB2 as intrinsic, instead of microenvironmentally-induced, EMT regulators, and vimentin as an in vivo indicator of EMT. CONCLUSIONS: Our findings provide insights into the characteristics and transcriptional regulators of spontaneous EMT in primary non-spindled carcinoma.
Assuntos
Neoplasias da Mama , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição , Transição Epitelial-Mesenquimal/genética , Humanos , Feminino , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Vimentina/metabolismo , Vimentina/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo , Linhagem Celular Tumoral , Animais , Camundongos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismoRESUMO
Epithelial-to-mesenchymal transition (EMT) contributes significantly to chemotherapy resistance and remains a critical challenge in treating advanced breast cancer. The complexity of EMT, involving redundant pro-EMT signaling pathways and its paradox reversal process, mesenchymal-to-epithelial transition (MET), has hindered the development of effective treatments. In this study, we utilized a Tri-PyMT EMT lineage-tracing model in mice and single-cell RNA sequencing (scRNA-seq) to comprehensively analyze the EMT status of tumor cells. Our findings revealed elevated ribosome biogenesis (RiBi) during the transitioning phases of both EMT and MET processes. RiBi and its subsequent nascent protein synthesis mediated by ERK and mTOR signalings are essential for EMT/MET completion. Importantly, inhibiting excessive RiBi genetically or pharmacologically impaired the EMT/MET capability of tumor cells. Combining RiBi inhibition with chemotherapy drugs synergistically reduced metastatic outgrowth of epithelial and mesenchymal tumor cells under chemotherapies. Our study suggests that targeting the RiBi pathway presents a promising strategy for treating patients with advanced breast cancer.
Although there have been considerable improvements in breast cancer treatments over the years, there are still many patients whose cancerous cells become resistant to treatments, including chemotherapy. Several different factors can contribute to resistance to chemotherapy, but one important change is the epithelial-to-mesenchymal transition (or EMT for short). During this transition, breast cancer cells become more aggressive, and more able to metastasize and spread to other parts of the body. Cells can also go through the reverse process called the mesenchymal-to-epithelial transition (or MET for short). Together, EMT and MET help breast cancer cells become resilient to treatment. However, it was not clear if these transitions shared a mechanism or pathway that could be targeted as a way to make cancer treatments more effective. To investigate, Ban, Zou et al. studied breast cancer cells from mice which had been labelled with fluorescent proteins that indicated whether a cell had ever transitioned between an epithelial and mesenchymal state. Various genetic experiments revealed that breast cancer cells in the EMT or MET phase made a lot more ribosomes, molecules that are vital for producing new proteins. Ban, Zhou et al. found that blocking the production of ribosomes (using drugs or genetic tools) prevented the cells from undergoing both EMT and MET. Further experiments showed that when mice with breast cancer were treated with a standard chemotherapy treatment plus an anti-ribosome drug, this reduced the number and size of tumors that had metastasized to the lung. This suggests that blocking ribosome production makes breast cancer cells undergoing EMT and/or MET less resistant to chemotherapy. Future studies will have to ascertain whether these findings also apply to patients with breast cancer. In particular, one of the drugs used to block ribosome production in this study is in early-phase clinical trials, so future trials may be able to assess the drug's effect in combination with chemotherapies.
Assuntos
Neoplasias da Mama , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Ribossomos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Camundongos , Feminino , Ribossomos/metabolismo , Ribossomos/efeitos dos fármacos , Humanos , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biogênese de Organelas , Transdução de Sinais/efeitos dos fármacosRESUMO
High tumor's lactate level directly associates with high tumor growth, metastasis, and patients' poor prognosis. Therefore, many studies have focused on the decrease of tumor's lactate as a novel cancer treatment. In the present study for the first time, a strictly anaerobic lactate-fermenting bacterium, Veillonella parvula, was employed for the decrease of tumor's lactate level. At first, 4T1 breast tumor-bearing BALB/c mice were administered with 106 V. parvula bacteria intravenously, orally, intraperitoneally, and intratumorally. Then, the bacteria biodistribution was evaluated. The best administration route according to tumor colonization was selected and its safety was assessed. Then, the therapeutic effect of V. parvula administration through the best route was investigated according to 4T1 murine breast tumor's growth and metastasis in vivo. In addition, histopathological and immunohistochemistry evaluations were done to estimate microscopic changes at the inner of the tumor and tumor's lactate level was measured after V. parvula administration. V. parvula exhibited considerable tumor-targeting and colonization efficacy, 24 h after intravenous administration. Normal organs were free of the bacteria after 72 h and no side effect was observed. Tumor colonization by V. parvula significantly decreased the tumors' lactate level for about 46% in comparison with control tumors which caused 44.3% and 51.6% decline (P < 0.05) in the mean tumors' volume and liver metastasis of the treatment group in comparison with the control group, respectively. The treatment group exhibited 35% inhibition in the cancer cell proliferation in comparison with the control according to the Ki-67 immunohistochemistry staining. Therefore, intravenous administration of V. parvula is a tumor-specific and safe treatment which can significantly inhibit tumors' growth and metastasis by decreasing the tumor lactate level.
Assuntos
Ácido Láctico , Camundongos Endogâmicos BALB C , Veillonella , Animais , Ácido Láctico/metabolismo , Camundongos , Feminino , Veillonella/metabolismo , Linhagem Celular Tumoral , Metástase Neoplásica , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismoRESUMO
BACKGROUND: Breast cancer (BRCA) remains to be among the main causes of cancer-associated mortality in women globally. HGH1 homolog (HGH1) has been reported to be associated with tumor immunity. However, the function of HGH1 in BRCA remains unclear. Therefore, the present study examined the potential role of HGH1 in BRCA. METHODS: The Cancer Genome Atlas (TCGA) databases and Gene Expression Omnibus (GEO) were used to obtain RNA-seq data for BRCA. A protein localization of HGH1 was determined by using the Human Protein Atlas (HPA), and immunohistochemistry (IHC) staining revealed an upregulation in the expression of HGH1 in clinical BRCA tissues. Xenograft mice were used to test tumor growth and HGH1 expression in breast cancer cells. The protein interaction information of HGH1 was analyzed using the GeneMANIA website. Based on univariate Cox regression and Kaplan-Meier methods, we evaluated the role of HGH1 in BRCA prognosis. HGH1-related differentially expressed genes were analyzed using GO, KEGG, and GSEA. We also examined the relationship between HGH1 expression, immune checkpoints, and immune infiltration. CCK-8, EdU, and colony formation assays were used to measure cell proliferation, and western blot analysis was used to evaluate HGH1's role in BRCA. RESULTS: IHC results showed that the expression of HGH1 was significantly upregulated in BRCA tissues compared to normal tissues. High levels of HGH1 expression was associated with worse clinical features and a worse prognosis. HGH1 expression was an independent predictor of BRCA outcomes in both univariate and multivariate analyses. Functionally, western blot analysis showed that HGH1 is implicated in cell cycle. As well, knocking down HGH1 significantly reduced BRCA cells' proliferative abilities. Crucially, HGH1 expression levels were positively correlated with Th2 cell infiltration and negatively correlated with Tcm cell infiltration. CONCLUSION: Biomarkers such as HGH1 can reliably predict prognosis in BRCA patients.
Assuntos
Neoplasias da Mama , Ciclo Celular , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Feminino , Prognóstico , Animais , Camundongos , Ciclo Celular/genética , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Linhagem Celular TumoralRESUMO
Breast cancer ranks as one of the most common malignancies among women, with its prognosis and therapeutic efficacy heavily influenced by factors associated with the tumor cell biology, particularly the tumor microenvironment (TME). The diverse elements of the TME are engaged in dynamic bidirectional signaling interactions with various pathways, which together dictate the growth, invasiveness, and metastatic potential of breast cancer. The Hedgehog (Hh) signaling pathway, first identified in Drosophila, has been established as playing a critical role in human development and disease. Notably, the dysregulation of the Hh pathway is recognized as a major driver in the initiation, progression, and metastasis of breast cancer. Consequently, elucidating the mechanisms by which the Hh pathway interacts with the distinct components of the breast cancer TME is essential for comprehensively evaluating the link between Hh pathway activation and breast cancer risk. This understanding is also imperative for devising novel targeted therapeutic strategies and preventive measures against breast cancer. In this review, we delineate the current understanding of the impact of Hh pathway perturbations on the breast cancer TME, including the intricate and complex network of intersecting signaling cascades. Additionally, we focus on the therapeutic promise and clinical challenges of Hh pathway inhibitors that target the TME, providing insights into their potential clinical utility and the obstacles that must be overcome to harness their full therapeutic potential.
Assuntos
Neoplasias da Mama , Proteínas Hedgehog , Transdução de Sinais , Microambiente Tumoral , Humanos , Proteínas Hedgehog/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Animais , FemininoRESUMO
Chemokines and their receptors are a family of chemotactic cytokines with important functions in the immune response in both health and disease. Their known physiological roles such as the regulation of leukocyte trafficking and the development of immune organs generated great interest when it was found that they were also related to the control of early and late inflammatory stages in the tumor microenvironment. In fact, in breast cancer, an imbalance in the synthesis of chemokines and/or in the expression of their receptors was attributed to be involved in the regulation of disease progression, including invasion and metastasis. Research in this area is progressing rapidly and the development of new agents based on chemokine and chemokine receptor antagonists are emerging as attractive alternative strategies. This chapter provides a snapshot of the different functions reported for chemokines and their receptors with respect to the potential to regulate breast cancer progression.