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1.
Dalton Trans ; 53(47): 18880-18889, 2024 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-39508517

RESUMO

For years, cancer has been the second cause of death worldwide, preceded by cardiovascular diseases only. The number of research groups focusing on the discovery of new drugs to treat cancer is growing and the aim is to look for more effective compounds that cause less severe side effects and do not suffer from therapeutic resistance. The metal complexes cisplatin and carboplatin are widely used in the chemotherapeutic treatment of various types of cancer, including triple-negative breast cancer (TNBC). Both compounds are essential in modern chemotherapy and continue to be the subject of research to optimize their therapeutic properties and minimize adverse effects. Laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) allows obtaining both quantitative data and information on the spatial distribution of elements in biological tissues and populations of single cells. In this work, the content of Pt and its distribution in TNBC MDA-MB-231 cells were determined via LA-ICP-MS analysis after incubation with different Pt-containing drugs. The quantitative analysis of single cells and the elemental maps revealing the distribution of Pt over and within the cells provide an enhanced insight into the potential mechanism of action of these Pt-containing drugs and their efficacy against TNBC.


Assuntos
Antineoplásicos , Terapia a Laser , Espectrometria de Massas , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Feminino , Carboplatina/farmacologia , Carboplatina/química , Cisplatino/farmacologia , Platina/química , Análise de Célula Única , Neoplasias da Mama/patologia , Neoplasias da Mama/tratamento farmacológico
2.
Int J Biochem Cell Biol ; 177: 106697, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39566654

RESUMO

Triple-negative breast cancer (TNBC) is an aggressive type of tumor that tends to recur in women. It is characterized by the absence of hormonal receptors, making it challenging to diagnosis and treatment. In this study, we investigated the anti-tumor effects of a pro-oxidant naphthoquinone derivative called bromo-naphthoquinone (BrNQ) isolated and combined with the antioxidant tannic acid (TA) in order to improve treatment. We used tumor cell lines MDA-MB-231 and HCC-70, as well as normal breast cells, HB4a, as control. Initially, viability assays conducted within 72 hours showed that the combination of compounds had a synergistic and notable cytotoxic effect on the tumor cells. The increased cytotoxicity appeared to be linked to changes in the cellular redox status, as indicated by a significant rise in reactive oxygen species (ROS) and though alterations in the level of thiol. The treatment also induced apoptosis, inhibited proliferation, and reduced migration, particularly in the MDA-MB-231 cell line. Furthermore, relevant changes were detected in the expression of Bcl-2, BAX, FAS, and BIRC-5, while no significant alteration in the expression of NOXs was observed. In conclusion, our findings suggested that the combination of BrNQ and TA though the ability to change redox status in tumor cells could act as a potential adjuvant treatment modality for improve prognosis in TNBC.


Assuntos
Apoptose , Naftoquinonas , Taninos , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Taninos/farmacologia , Naftoquinonas/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Proliferação de Células/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Antineoplásicos/farmacologia , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Polifenóis
3.
J Biomed Sci ; 31(1): 93, 2024 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-39354523

RESUMO

Triple-negative breast cancer (TNBC), characterized by high invasiveness, is associated with poor prognosis and elevated mortality rates. Despite the development of effective therapeutic targets for TNBC, systemic chemotherapy and radiotherapy (RdT) remain prevalent treatment modalities. One notable challenge of RdT is the acquisition of radioresistance, which poses a significant obstacle in achieving optimal treatment response. Compelling evidence implicates non-coding RNAs (ncRNAs), gene expression regulators, in the development of radioresistance. This systematic review focuses on describing the role, association, and/or involvement of ncRNAs in modulating radioresponse in TNBC. In adhrence to the PRISMA guidelines, an extensive and comprehensive search was conducted across four databases using carefully selected entry terms. Following the evaluation of the studies based on predefined inclusion and exclusion criteria, a refined selection of 37 original research articles published up to October 2023 was obtained. In total, 33 different ncRNAs, including lncRNAs, miRNAs, and circRNAs, were identified to be associated with radiation response impacting diverse molecular mechanisms, primarily the regulation of cell death and DNA damage repair. The findings highlighted in this review demonstrate the critical roles and the intricate network of ncRNAs that significantly modulates TNBC's responsiveness to radiation. The understanding of these underlying mechanisms offers potential for the early identification of non-responders and patients prone to radioresistance during RdT, ultimately improving TNBC survival outcomes.


Assuntos
RNA não Traduzido , Neoplasias de Mama Triplo Negativas , Feminino , Humanos , Tolerância a Radiação/genética , RNA não Traduzido/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/radioterapia
4.
Rev Invest Clin ; 76(4): 185-194, 2024 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-39419019

RESUMO

Background: Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer (BC), characterized by a dismal prognosis. Dysregulated long non-coding RNA LINC01614 might be a potential biomarker for BC as previously reported. Nevertheless, its functions and mechanism in TNBC cells are unclear. Objectives: The study aimed to study the effects of LINC01614 on TNBC cell migration, invasion, and epithelial-mesenchymal transition (EMT) process as well as the related mechanism. Methods: Reverse transcription quantitative polymerase chain reaction was performed to detect the expression of LINC01614 and SP1 in TNBC cells and tissues. The cellular localization of LINC01614 was determined by subcellular fraction assays. Cell counting kit-8 and Transwell invasion assays were conducted for measurement of TNBC cell viability and invasive ability. Cell migration was performed using wound healing assays and Transwell migration assays. Chromatin immunoprecipitation assays and luciferase reporter assays were used to explore the interaction between SP1 and LINC01614. Western blotting was used to assess protein levels of factors involved in EMT process and Wnt/ß-catenin signaling in TNBC cells. Results: LINC01614 expression was elevated in TNBC tissues and cells. LINC01614 knockdown inhibited cell viability as well as migratory and invasive abilities of TNBC cells. LINC01614 knockdown also obstructed EMT process, as shown by E-cadherin upregulation and vimentin downregulation in TNBC cells. SP1 directly bound to the promoter of LINC01614 and activated LINC01614 expression. SP1 overexpression reversed the suppressive effect of LINC01614 knockdown on TNBC cell migration, invasion, and EMT process. Protein levels of Wnt and ß-catenin were diminished by LINC01614 knockdown, and the trend was partially rescued by SP1 overexpression. Conclusion: SP1-induced LINC01614 promoted malignant behavior of TNBC cells by activating the Wnt/ß-catenin signaling pathway.


Assuntos
Invasividade Neoplásica , RNA Longo não Codificante , Fator de Transcrição Sp1 , Neoplasias de Mama Triplo Negativas , Via de Sinalização Wnt , Feminino , Humanos , Linhagem Celular Tumoral , Movimento Celular , Sobrevivência Celular/genética , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Invasividade Neoplásica/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Fator de Transcrição Sp1/metabolismo , Fator de Transcrição Sp1/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Via de Sinalização Wnt/fisiologia , Via de Sinalização Wnt/genética
5.
Int J Mol Sci ; 25(19)2024 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-39409041

RESUMO

Within the field of nanomedicine, which is revolutionizing cancer treatment, solid lipid nanoparticles (SLNs) have shown advantages over conventional chemotherapy when tested on cancer cells in preclinical studies. SLNs have proven to be an innovative strategy for the treatment of triple-negative breast cancer cells, providing greater efficiency than existing treatments in various studies. The encapsulation of antineoplastic drugs in SLNs has facilitated a sustained, controlled, and targeted release, which enhances therapeutic efficiency and reduces adverse effects. Moreover, the surface of SLNs can be modified to increase efficiency. For instance, the coating of these particles with polyethylene glycol (PEG) decreases their opsonization, resulting in a longer life in the circulatory system. The creation of positively charged cationic SLNs (cSLNs), achieved by the utilization of surfactants or ionic lipids with positively charged structural groups, increases their affinity for cell membranes and plasma proteins. Hyaluronic acid has been added to SLNs so that the distinct pH of tumor cells would stimulate the release of the drug and/or genetic material. The current review summarizes the recent research on SLNs, focusing on the encapsulation and transport of therapeutic agents with a cytotoxic effect on triple-negative breast cancer.


Assuntos
Antineoplásicos , Lipídeos , Nanopartículas , Neoplasias de Mama Triplo Negativas , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Humanos , Nanopartículas/química , Feminino , Lipídeos/química , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/química , Portadores de Fármacos/química , Animais , Sistemas de Liberação de Medicamentos , Nanomedicina/métodos , Lipossomos
6.
Adv Med Sci ; 69(2): 398-406, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39233278

RESUMO

PURPOSE: Patients bearing estrogen receptor (ER)α-negative breast cancer tumors confront poor prognosis and are typically unresponsive to hormone therapy. Previous studies have shown that calcitriol, the active vitamin D metabolite, can induce ERα expression in ERα-negative cells. EB1089, a calcitriol analog with reduced calcemic effects, exhibits greater potency than calcitriol in inhibiting cancer cell growth. However, the impact of EB1089 on ERα expression in triple-negative breast cancer (TNBC) cells remains unexplored. This study aims to investigate whether EB1089 could induce functional ERα expression in TNBC cell lines, potentially enabling the antiproliferative effects of antiestrogens. MATERIALS AND METHODS: TNBC cell lines HCC1806 and HCC1937 were treated with EB1089, and ERα expression was analyzed using real-time PCR and Western blots. The transcriptional activity of induced ERα was evaluated through a luciferase reporter assay. The antiproliferative effects of tamoxifen and fulvestrant antiestrogens were assessed using the sulforhodamine B assay in the EB1089-treated cells. RESULTS: Our findings indicated that EB1089 significantly induced ERα mRNA and protein expression in TNBC cells. Moreover, EB1089-induced ERα exhibited transcriptional activity and effectively restored the inhibitory effects of antiestrogens, thereby suppressing cell proliferation in TNBC cells. CONCLUSION: EB1089 induced the expression of functional ERα in TNBC cells, restoring the antiproliferative effects of antiestrogens. These results highlight the potential of using EB1089 as a promising strategy for re-establishment of the antiproliferative effect of antiestrogens as a possible management for TNBC. This research lays the foundation for potential advancements in TNBC treatment, offering new avenues for targeted and effective interventions.


Assuntos
Proliferação de Células , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Proliferação de Células/efeitos dos fármacos , Feminino , Moduladores de Receptor Estrogênico/farmacologia , Receptor alfa de Estrogênio/metabolismo , Receptor alfa de Estrogênio/genética , Linhagem Celular Tumoral , Calcitriol/farmacologia , Calcitriol/análogos & derivados , Antagonistas de Estrogênios/farmacologia , Células Tumorais Cultivadas , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Colecalciferol/análogos & derivados
7.
Arch Pharm (Weinheim) ; 357(11): e2400316, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39252689

RESUMO

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is mainly treated with cytotoxic chemotherapy. However, this treatment is not always effective, and an important percentage of patients develop recurrence. Nanomaterials are emerging as alternative treatment options for various diseases, including cancer. This work reports the synthesis, characterization, antitumor activity evaluation, and sub-acute toxicity studies of two formulations based on amorphous silica nanoparticles (SiNPs). They are functionalized with 3-aminopropyltriethoxisilane (Si@NH2) and folic acid (FA; Si@FA). The results show that SiNPs reduce the viability and migration of TNBC MDA-MB-231 and 4T1 cell lines and Si@FA do not affect the growth of the mammary nonmalignant HC11 cells. In addition, Si@FA induces reactive oxygen species (ROS) generation and displays antiproliferative and subsequently proapoptotic effects in MDA-MB-231 cells. Moreover, none of the SiNPs cause signs of sub-acute toxicity in mice when administered at 30 mg/kg over a month. In conclusion, these nanosystems display intrinsic antitumor activity without causing toxic in vivo effects, being a promising therapeutic alternative for TNBC.


Assuntos
Antineoplásicos , Apoptose , Proliferação de Células , Sobrevivência Celular , Ácido Fólico , Nanopartículas , Espécies Reativas de Oxigênio , Dióxido de Silício , Neoplasias de Mama Triplo Negativas , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Dióxido de Silício/química , Nanopartículas/química , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Animais , Feminino , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Ácido Fólico/química , Ácido Fólico/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Silanos/química , Silanos/farmacologia , Propilaminas/química , Propilaminas/farmacologia , Propilaminas/síntese química , Relação Dose-Resposta a Droga
8.
Int J Mol Sci ; 25(16)2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39201489

RESUMO

Triple-negative breast cancer (TNBC), accounting for 15-20% of all breast cancers, has one of the poorest prognoses and survival rates. Metastasis, a critical process in cancer progression, causes most cancer-related deaths, underscoring the need for alternative therapeutic approaches. This study explores the anti-migratory, anti-invasive, anti-tumoral, and antimetastatic effects of copper coordination compounds Casiopeína IIIia (CasIIIia) and Casiopeína IIgly (CasIIgly) on MDA-MB-231 and 4T1 breast carcinoma cell lines in vitro and in vivo. These emerging anticancer agents, mixed chelate copper(II) compounds, induce apoptosis by generating reactive oxygen species (ROS) and causing DNA damage. Whole-transcriptome analysis via gene expression arrays indicated that subtoxic concentrations of CasIIIia upregulate genes involved in metal response mechanisms. Casiopeínas® reduced TNBC cell viability dose-dependently and more efficiently than Cisplatin. At subtoxic concentrations (IC20), they inhibited random and chemotactic migration of MDA-MB-231 and 4T1 cells by 50-60%, similar to Cisplatin, as confirmed by transcriptome analysis. In vivo, CasIIIia and Cisplatin significantly reduced tumor growth, volume, and weight in a syngeneic breast cancer model with 4T1 cells. Furthermore, both compounds significantly decreased metastatic foci in treated mice compared to controls. Thus, CasIIIia and CasIIgly are promising chemotherapeutic candidates against TNBC.


Assuntos
Antineoplásicos , Cobre , Neoplasias de Mama Triplo Negativas , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Humanos , Feminino , Cobre/química , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Quelantes/farmacologia , Apoptose/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/uso terapêutico , Movimento Celular/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Dano ao DNA/efeitos dos fármacos
9.
Clinics (Sao Paulo) ; 79: 100479, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39208653

RESUMO

OBJECTIVES: To identify somatic mutations in tumors from young women with triple-negative or luminal breast cancer, through targeted sequencing and to explore the cancer driver potential of these gene variants. METHODS: A customized gene panel was assembled based on data from previous sequencing studies of breast cancer from young women. Triple-negative and luminal tumors and paired blood samples from young breast cancer patients were sequenced, and identified gene variants were searched for their driver potential, in databases and literature. Additionally, the authors performed an exploratory analysis using large, curated databases to evaluate the frequency of somatic mutations in this gene panel in tumors stratified by age groups (every 10 years). RESULTS: A total of 28 young women had their tumoral tissue and blood samples sequenced. Using a customized panel of 64 genes, the authors could detect cancer drivers in 11/12 (91.7 %) TNBC samples and 11/16 (68.7 %) luminal samples. Among TNBC patients, the most frequent cancer driver was TP53, followed by NF1, NOTCH1 and PTPN13. In luminal samples, PIK3CA and GATA3 were the main cancer drivers, and other drivers were GRHL2 and SMURF2. CACNA1E was involved in both TN and luminal BC. The exploratory analysis also indicated a role for SMURF2 in luminal BC development in young patients. CONCLUSIONS: The data further indicates that some cancer drivers are more common in a specific breast cancer subtype from young patients, such as TP53 in TNBC and PIK3CA and GATA3 in luminal samples. These results also provide additional evidence that some genes not considered classical cancer-causing genes, such as CACNA1E, GRHL2 and SMURF2 might be cancer drivers in this age group.


Assuntos
Mutação , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Neoplasias de Mama Triplo Negativas/genética , Adulto , Neoplasias da Mama/genética , Brasil , Adulto Jovem , Pessoa de Meia-Idade , Fatores Etários , Biomarcadores Tumorais/genética
10.
Int J Mol Sci ; 25(15)2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-39126001

RESUMO

Breast cancer is the most diagnosed type of cancer worldwide and the second cause of death in women. Triple-negative breast cancer (TNBC) is the most aggressive, and due to the lack of specific targets, it is considered the most challenging subtype to treat and the subtype with the worst prognosis. The present study aims to determine the antitumor effect of beta-D-glucose-reduced silver nanoparticles (AgNPs-G) in a murine model of TNBC, as well as to study its effect on the tumor microenvironment. In an airbag model with 4T1 tumor cell implantation, the administration of AgNPs-G or doxorubicin showed antitumoral activity. Using immunohistochemistry it was demonstrated that treatment with AgNPs-G decreased the expression of PCNA, IDO, and GAL-3 and increased the expression of Caspase-3. In the tumor microenvironment, the treatment increased the percentage of memory T cells and innate effector cells and decreased CD4+ cells and regulatory T cells. There was also an increase in the levels of TNF-α, IFN-γ, and IL-6, while TNF-α was increased in serum. In conclusion, we suggest that AgNPs-G treatment has an antitumor effect that is demonstrated by its ability to remodel the tumor microenvironment in mice with TNBC.


Assuntos
Glucose , Nanopartículas Metálicas , Prata , Neoplasias de Mama Triplo Negativas , Microambiente Tumoral , Animais , Microambiente Tumoral/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Prata/química , Nanopartículas Metálicas/química , Feminino , Camundongos , Glucose/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Camundongos Endogâmicos BALB C , Doxorrubicina/farmacologia , Humanos
11.
Artigo em Inglês | MEDLINE | ID: mdl-39176205

RESUMO

Objective: Neoadjuvant chemotherapy (NACT) has become the standard of care for patients with triple-negative breast cancer (TNBC) with tumors > 1 cm or positive axillary nodes. Pathologic complete response (pCR) has been used as an endpoint to select patients for treatment scaling. This study aimed to examine the benefit of adding adjuvant capecitabine for TNBC patients who did not achieve pCR after standard NACT in a real-world scenario. Methods: This retrospective cohort study included all patients with TNBC who underwent NACT between 2010 and 2020. Clinicopathological data were obtained from the patient records. Univariate and multivariate analyses were conducted at the 5 years follow-up period. Results: We included 153 patients, more than half of whom had stage III (58.2%) and high-grade tumors (60.8%). The overall pCR rate was 34.6%, and 41% of the patients with residual disease received adjuvant capecitabine. Disease-specific survival (DSS) among the patients who achieved pCR was significantly higher (p<0.0001). Residual disease after NACT was associated with detrimental effects on DSS. In this cohort, we did not observe any survival benefit of adding adjuvant capecitabine for patients with TNBC subjected to NACT who did not achieve pCR (p=0.52). Conclusion: Our study failed to demonstrate a survival benefit of extended capecitabine therapy in patients with TNBC with residual disease after NACT. More studies are warranted to better understand the indication of systemic treatment escalation in this scenario.


Assuntos
Capecitabina , Terapia Neoadjuvante , Neoplasias de Mama Triplo Negativas , Humanos , Capecitabina/administração & dosagem , Capecitabina/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Quimioterapia Adjuvante , Adulto , Antimetabólitos Antineoplásicos/uso terapêutico , Antimetabólitos Antineoplásicos/administração & dosagem , Idoso
12.
Mol Cancer Ther ; 23(11): 1613-1625, 2024 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-39087451

RESUMO

Triple negative breast cancer (TNBC) represents a therapeutic challenge in which standard chemotherapy is limited to paclitaxel. MBQ167, a clinical stage small molecule inhibitor that targets Rac and Cdc42, inhibits tumor growth and metastasis in mouse models of TNBC. Herein, we investigated the efficacy of MBQ167 in combination with paclitaxel in TNBC preclinical models, as a prelude to safety trials of this combination in patients with advanced breast cancer. Individual MBQ167 or combination therapy with paclitaxel was more effective at reducing TNBC cell viability and increasing apoptosis compared with paclitaxel alone. In orthotopic mouse models of human TNBC (MDA-MB231 and MDA-MB468), individual MBQ167, paclitaxel, or the combination reduced mammary tumor growth with similar efficacy, with no apparent liver toxicity. However, paclitaxel single agent treatment significantly increased lung metastasis, whereas MBQ167, single or combined, reduced lung metastasis. In the syngeneic 4T1/BALB/c model, combined MBQ167 and paclitaxel decreased established lung metastases by ∼80%. To determine the molecular basis for the improved efficacy of the combined treatment on metastasis, 4T1 tumor extracts from BALB/c mice treated with MBQ167, paclitaxel, or the combination were subjected to transcriptomic analysis. Gene set enrichment identified specific downregulation of central carbon metabolic pathways by the combination of MBQ167 and paclitaxel but not individual compounds. Biochemical validation, by immunoblotting and metabolic Seahorse analysis, shows that combined MBQ167 and paclitaxel reduces glycolysis. This study provides a strong rationale for the clinical testing of MBQ167 in combination with paclitaxel as a potential therapeutic for TNBC and identifies a unique mechanism of action.


Assuntos
Paclitaxel , Paclitaxel/farmacologia , Animais , Humanos , Camundongos , Feminino , Carbono , Linhagem Celular Tumoral , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos BALB C , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Proteínas rac de Ligação ao GTP/metabolismo , Proteínas rac de Ligação ao GTP/antagonistas & inibidores
13.
Rev Med Inst Mex Seguro Soc ; 62(1): 1-7, 2024 Jan 08.
Artigo em Espanhol | MEDLINE | ID: mdl-39110839

RESUMO

Background: Primary breast tumors with neuroendocrine (NE) differentiation are a heterogeneous tumor group with diversity of biological behavior, with poorly defined prevalence and prognosis. Objective: To evaluate the chromogranin, synaptophysin, CD56, INSM1 markers expression prevalence and the association between NE differentiation and tumor molecular type. Material and methods: Observational, cross-sectional study which included 110 breast tissue samples with primary invasive carcinoma. Immunohistochemistry was performed for chromogranin, synaptophysin, CD56 and INMS1 markers. NE differentiation was considered with 10-90% positive cells, and NE tumor with > 90% positive cells. Results: 26.3% showed neuroendocrine differentiation. Out of these, 48.2% were luminal-A type, 24.1% luminal-B, 11.5% HER2neu, 17.2% triple-negative; 1.8% were NE tumors. Tumors were marker positive, and out of these to chromogranin in 24.5%, synaptophysin in 28.2%, CD56 in 2.7%, INSM1 in 16.4%. Synaptophysin was expressed in 17.3% luminal-A type, 6.4% luminal-B, 0.9% HER2neu, 3.6% triple-negative. NE differentiation showed association with synaptophysin expression (r = 0.586, p = 0.0001). Conclusion: The NE differentiation prevalence was 26.3% in primary invasive breast cancers, with luminal-A molecular type predominance.


Introducción: los tumores primarios de mama con diferenciación neuroendócrina (NEBC por sus siglas en inglés) son un grupo heterogéneo de tumores con diversidad de comportamiento biológico, con prevalencia y pronóstico poco definido. Objetivo: evaluar la prevalencia de la expresión los marcadores cromogranina, sinaptofisina, CD56, INSM1 y la asociación entre la diferenciación neuroendócrina y el tipo molecular del tumor. Material y métodos: estudio observacional, transversal que incluyó 110 muestras de tejido mamario con carcinoma invasor primario. Se realizó inmunohistoquímica para los marcadores cromogranina, sinaptofisina, CD56 y INMS1. La presencia 10-90% de células positivas se consideró diferenciación neuroendócrina y tumor neuroendócrino con > 90% de células positivas. Resultados: el 26.3% mostró diferenciación neuroendócrina. De estos, 48.2% fueron tipo luminal-A, 24.1% luminal-B, 11.5% HER2neu y 17.2% triple-negativo; 1.8% resultaron tumores neuroendócrinos. Los tumores presentaron marcadores positivos y de estos, 24.5% fueron a cromogranina, 28.2% a sinaptofisina, 2.7% a CD56 y 16.4% a INSM1. La sinaptofisina se expresó en 17.3% del tipo luminal-A, 6.4% luminal-B, 0.9% HER2neu, 3.6% triple-negativo. La diferenciación neuroendócrina mostró asociación con la expresión de sinaptofisina (r = 0.586, p = 0.0001). Conclusión: la prevalencia de la diferenciación neuroendócrina fue del 26.3% en los cánceres invasores primarios de mama, con predominio en el tipo molecular luminal-A.


Assuntos
Biomarcadores Tumorais , Sinaptofisina , Humanos , Feminino , Estudos Transversais , Biomarcadores Tumorais/metabolismo , Pessoa de Meia-Idade , Adulto , Sinaptofisina/metabolismo , Idoso , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Antígeno CD56/metabolismo , Imuno-Histoquímica , Proteínas Repressoras/metabolismo , Cromograninas/metabolismo , Receptor ErbB-2/metabolismo , Idoso de 80 Anos ou mais
14.
Sci Rep ; 14(1): 20253, 2024 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-39215068

RESUMO

Tumor metabolism is a crucial aspect of cancer development, and mitochondria plays a significant role in the aggressiveness and metastasis of tumors. As a result, mitochondria have become a promising therapeutic target in cancer treatment, leading to the development of compounds known as mitocans. In our group, we have consolidated the search of anticancer therapies based on natural products derived from plants, obtaining extracts such as P2Et from Caesalpinia spinosa and Anamu-SC from Petiveria alliacea, which have been shown to have antitumor activities in different cancer models. These extracts, due to their complex molecular composition, can interfere with multiple functions during tumor progression. To better understand how these natural products operate (P2Et and Anamu-SC), we constructed a model using 4T1 murine breast cancer cells with reduced expression of genes associated with glycolysis (Hexokinase-2) and mitochondrial function (Cqbp). The results indicate that the cells were more sensitive to the Anamu-SC extract, showing significant decreases in glucose consumption, ATP production, and oxygen consumption rate. Additionally, we observed changes in mitochondrial function, which reduced the cells' ability to migrate, particularly when C1qbp was silenced. This triple-negative breast cancer model allows us to identify potential natural products that can modulate tumor cell metabolism.


Assuntos
Movimento Celular , Mitocôndrias , Extratos Vegetais , Neoplasias de Mama Triplo Negativas , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Animais , Movimento Celular/efeitos dos fármacos , Camundongos , Feminino , Linhagem Celular Tumoral , Humanos , Glicólise/efeitos dos fármacos , Fabaceae/química
15.
Nat Commun ; 15(1): 5694, 2024 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-38972873

RESUMO

Tumor-associated myeloid-derived cells (MDCs) significantly impact cancer prognosis and treatment responses due to their remarkable plasticity and tumorigenic behaviors. Here, we integrate single-cell RNA-sequencing data from different cancer types, identifying 29 MDC subpopulations within the tumor microenvironment. Our analysis reveals abnormally expanded MDC subpopulations across various tumors and distinguishes cell states that have often been grouped together, such as TREM2+ and FOLR2+ subpopulations. Using deconvolution approaches, we identify five subpopulations as independent prognostic markers, including states co-expressing TREM2 and PD-1, and FOLR2 and PDL-2. Additionally, TREM2 alone does not reliably predict cancer prognosis, as other TREM2+ macrophages show varied associations with prognosis depending on local cues. Validation in independent cohorts confirms that FOLR2-expressing macrophages correlate with poor clinical outcomes in ovarian and triple-negative breast cancers. This comprehensive MDC atlas offers valuable insights and a foundation for futher analyses, advancing strategies for treating solid cancers.


Assuntos
Glicoproteínas de Membrana , Células Mieloides , Neoplasias , Receptores Imunológicos , Análise de Célula Única , Microambiente Tumoral , Humanos , Análise de Célula Única/métodos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Células Mieloides/metabolismo , Células Mieloides/patologia , Receptores Imunológicos/metabolismo , Receptores Imunológicos/genética , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Prognóstico , Neoplasias/genética , Neoplasias/patologia , Neoplasias/metabolismo , Feminino , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/genética , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética
17.
Cell Biochem Biophys ; 82(4): 3507-3516, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39033092

RESUMO

Unbalanced redox status and constitutive STAT3 activation are related to several aspects of tumor biology and poor prognosis, including metastasis and drug resistance. The triple-negative breast cancer (TNBC) is listed as the most aggressive and exhibits the worst prognosis among the breast cancer subtypes. Although the mechanism of reactive oxygen species (ROS) generation led to STAT3 activation is described, there is no data concerning the STAT3 influence on redox homeostasis in TNBC. To address the role of STAT3 signaling in redox balance, we inhibited STAT3 in TNBC cells and investigated its impact on total ROS levels, contents of hydroperoxides, nitric oxide (NO), and total glutathione (GSH), as well as the expression levels of 3-nitrotyrosine (3NT), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), and nuclear factor kappa B (NF-κB)/p65. Our results indicate that ROS levels depend on the STAT3 activation, while the hydroperoxide level remained unchanged, and NO and 3NT expression increased. Furthermore, GSH levels, Nrf2, and NF-κB/p65 protein levels are decreased in the STAT3-inhibited cells. Accordingly, TNBC patients' data from TCGA demonstrated that both STAT3 mRNA levels and STAT3 signature are correlated to NF-κB/p65 and Nrf2 signatures. Our findings implicate STAT3 in controlling redox balance and regulating redox-related genes' expression in triple-negative breast cancer.


Assuntos
Glutationa , Fator 2 Relacionado a NF-E2 , Oxirredução , Espécies Reativas de Oxigênio , Fator de Transcrição STAT3 , Neoplasias de Mama Triplo Negativas , Humanos , Fator de Transcrição STAT3/metabolismo , Linhagem Celular Tumoral , Glutationa/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Espécies Reativas de Oxigênio/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Feminino , Óxido Nítrico/metabolismo , Tirosina/metabolismo , Tirosina/análogos & derivados , Fator de Transcrição RelA/metabolismo , Transdução de Sinais
18.
Sci Rep ; 14(1): 15982, 2024 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-38987610

RESUMO

The search for prognostic markers in breast cancer has bumped into a typical feature of these tumors, intra and intertumoral heterogeneity. Changes in the expression profile, localization of these proteins or shedding to the surrounding stroma can be useful in the search for new markers. In this context, classification by molecular subtypes can bring perspectives for both diagnosis and screening for appropriate treatments. However, the Triple Negative (TN) subtype, which is already the one with the worst prognosis, lacks appropriate and consistent molecular markers. In this work, we analyzed 346 human breast cancer samples in tissue microarrays (TMA) from cases diagnosed with invasive breast carcinoma to assess the expression and localization pattern of Maspin and their correlation with clinical parameters. To complement our findings, we also used TCGA data to analyze the mRNA levels of these respective genes. Our data suggests that the TN subtype demonstrates a higher level of cytoplasmic Maspin compared to the other subtypes. Maspin transcript levels follow the same trend. However, TN patients with lower Maspin expression tend to have worse overall survival and free-survival metastasis rates. Finally, we used Maspin expression data to verify possible relationships with the clinicopathological information of our cohort. Our univariate analyses indicate that Maspin is related to the expression of estrogen receptor (ER) and progesterone receptor (PR). Furthermore, Maspin expression levels also showed correlation with Scarff-Bloom-Richardson (SBR) parameter, and stromal Maspin showed a relationship with lymph node involvement. Our data is not consistently robust enough to categorize Maspin as a prognostic marker. However, it does indicate a change in the expression profile within the TN subtype.


Assuntos
Biomarcadores Tumorais , Serpinas , Neoplasias de Mama Triplo Negativas , Humanos , Serpinas/metabolismo , Serpinas/genética , Feminino , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/mortalidade , Prognóstico , Pessoa de Meia-Idade , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Idoso , Adulto , Receptores de Progesterona/metabolismo , Receptores de Progesterona/genética , Receptores de Estrogênio/metabolismo , Regulação Neoplásica da Expressão Gênica
19.
Clin Breast Cancer ; 24(7): e633-e644.e2, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38997857

RESUMO

BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. FAM3B, a secreted protein, has been extensively studied in various types of tumors. However, its function in breast cancer remains poorly understood. METHODS: We analyzed FAM3B expression data from breast cancer patients available at TCGA database and overall survival was analyzed by using the Kaplan-Meier plotter. MDA-MB-231 TNBC tumor cell line and hormone-responsive MCF-7 cell lines were transfected to overexpress FAM3B. We assessed cell death, tumorigenicity, and invasiveness in vitro through MTT analysis, flow cytometry assays, anchorage-independent tumor growth, and wound healing assays, respectively. We performed in vivo evaluation by tumor xenograft in nude mice. RESULTS: In silico analysis revealed that FAM3B expression was lower in all breast tumors. However, TNBC patients with high FAM3B expression had a poor prognosis. FAM3B overexpression protected MDA-MB-231 cells from cell death, with increased expression of Bcl-2 and Bcl-xL, and reduced caspase-3 activity. MDA-MB-231 cells overexpressing FAM3B also exhibited increased tumorigenicity and migration rates in vitro, displaying increased tumor growth and reduced survival rates in xenotransplanted nude mice. This phenotype is accompanied by the upregulation of EMT-related genes Slug, Snail, TGFBR2, vimentin, N-cadherin, MMP-2, MMP-9, and MMP-14. However, these effects were not observed in the MCF-7 cells overexpressing FAM3B. CONCLUSION: FAM3B overexpression contributes to tumor growth, promotion of metastasis, and, consequently, leads to a poor prognosis in the most aggressive forms of breast cancer. Future clinical research is necessary to validate FAM3B as both a diagnostic and a therapeutic strategy for TNBC.


Assuntos
Apoptose , Camundongos Nus , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Animais , Feminino , Camundongos , Prognóstico , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Movimento Celular , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Citocinas/metabolismo
20.
Mar Drugs ; 22(6)2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38921562

RESUMO

Experiments conducted on triple-negative breast cancer have shown that fucoidan from Lessonia trabeculata (FLt) exhibits cytotoxic and antitumor properties. However, further research is necessary to gain a complete understanding of its bioactivity and level of cytotoxicity. The cytotoxic effect of FLt was determined by the 2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Apoptosis was analyzed using annexin V and caspase 3/7 staining kit and DNA fragmentation. In addition, transcriptional expression of antiapoptotic (Bcl-2 and XIAP) and proapoptotic (caspase 8, caspase 9, and AIF) genes were analyzed in TNBC 4T1 cells. After 72 h of culture, the IC50 for FLt was 561 µg/mL, while doxorubicin (Dox) had an IC50 of 0.04 µg/mL. In addition, assays for FLt + Dox were performed. Annexin V and caspase 3/7 revealed that FLt induces early and late-stage apoptosis. DNA fragmentation results support necrotic death of 4T1 cells. Similarly, transcripts that prevent cell death were decreased, while transcripts that promote cell death were increased. This study showed that FLt induces apoptosis by both caspase-dependent and caspase-independent mechanisms. These findings suggest that FLt may have potential applications in breast cancer treatment. Further research will provide more information to elucidate the mechanism of action of FLt.


Assuntos
Apoptose , Caspases , Polissacarídeos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Polissacarídeos/farmacologia , Animais , Feminino , Caspases/metabolismo , Camundongos , Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Humanos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Fragmentação do DNA/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Kelp
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