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1.
Mol Cell Endocrinol ; 559: 111792, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36309204

RESUMO

Pigment epithelium-derived factor (PEDF) has a critical role in bone development and anti-tumour function in breast cancer (BC). As the expression and role of PEDF in BC bone metastases is unknown, we aimed to characterise PEDF in primary and metastatic BC. Subcellular PEDF localisation was semi-quantitatively analysed via immunohistochemistry in patient-matched, archived formalin-fixed paraffin-embedded primary BC and liver, lung, and decalcified bone metastases specimens. PEDF localisation was evaluated in 23 metastatic BC patients diagnosed with ER+, human epidermal growth factor receptor-2 (HER2) negative BC or TNBC. Cytoplasmic (p = 0.019) and membrane (p = 0.048) PEDF was lower in bone metastases compared to primary ER+/HER2- BC. In contrast, nuclear PEDF scores were higher in metastases compared to primary TNBC (p = 0.027), and increased membrane PEDF in metastatic tissue had improved disease-free interval (p = 0.016). Nuclear PEDF was decreased in bone metastases compared to primary ER+//HER2- BC in post-menopausal patients (p = 0.029). These novel findings indicate PEDF plays a role in clinical BC metastasis. Significantly lower PEDF levels in the post-menopausal compared to pre-menopausal setting suggests future PEDF research may have greater clinical importance in the post-menopausal ER+/HER2- BC population.


Assuntos
Neoplasias Ósseas , Neoplasias da Mama , Serpinas , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Neoplasias da Mama/patologia , Receptores de Estrogênio/metabolismo , Regulação para Baixo , Proteínas do Olho , Menopausa
2.
Gene ; 850: 146930, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36195266

RESUMO

Resistance to cancer therapeutics represents a leading cause of mortality and is particularly important in cancers, such as triple negative breast cancer, for which no targeted therapy is available, as these are only treated with traditional chemotherapeutics. Cancer, as well as bacterial, drug resistance can be intrinsic, acquired or adaptive. Adaptive cancer drug resistance is gaining attention as a mechanism for the generation of long-term drug resistance as is the case with bacterial antibiotic resistance. We have used a cellular model of triple negative breast cancer (CAL51) and its drug resistance derivative (CALDOX) to gain insight into genome-wide expression changes associated with long-term doxorubicin (a widely used anthracycline for cancer treatment) resistance and doxorubicin-induced stress. Previous work indicates that both naïve and resistance cells have a functional p53-p21 axis controlling cell cycle at G1, although this is not a driver for drug resistance, but down-regulation of TOP2A (topoisomerase IIα). As expected, CALDOX cells have a signature characterized, in addition to down-regulation of TOP2A, by genes and pathways associated with drug resistance, metastasis and stemness. Both CAL51 and CALDOX stress signatures share 12 common genes (TRIM22, FAS, SPATA18, SULF2, CDKN1A, GDF15, MYO6, CXCL5, CROT, EPPK1, ZMAT3 and CD44), with roles in the above-mentioned pathways, indicating that these cells have similar functional responses to doxorubicin relaying on the p53 control of apoptosis. Eight genes are shared by both drug stress signatures (in CAL51 and CALDOX cells) and CALDOX resistant cells (FAS, SULF2, CDKN1A, CXCL5, CD44, SPATA18, TRIM22 and CROT), many of them targets of p53. This corroborates experimental data indicating that CALDOX cells, even in the absence of drug, have activated, at least partially, the p53-p21 axis and DNA damage response. Although this eight-gene signature might be an indicator of adaptive resistance, as this transient phenomenon due to short-term stress may not revert to its original state upon withdrawal of the stressor, previous experimental data indicates that the p53-p21 axis is not responsible for doxorubicin resistance. Importantly, TOP2A is not responsive to doxorubicin treatment and thus absent in both drug stress signatures. This indicates that during the generation of doxorubicin resistance, cells acquire genetic changes likely to be random, leading to down regulation of TOP2A, but selected during the generation of cells due to the presence of drug in the culture medium. This poses a considerable constraint for the development of strategies aimed at avoiding the emergence of drug resistance in the clinic.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética
3.
Hematol Oncol Clin North Am ; 37(1): 133-150, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36435606

RESUMO

For women with triple-negative breast cancer, the addition of pembrolizumab to chemotherapy has become a standard of care in the early-stage and first-line metastatic setting. However, many questions persist. Different chemotherapy backbones and sequencing strategies have been evaluated, but evidence supporting the superiority of one over the other is weak. Although many have been investigated, programmed cell death ligand 1 (PDL1) is the only approved biomarker. Since immunotherapy has been associated with potentially severe and permanent toxicities, the identification of better predictive biomarkers is essential. New strategies are needed to increase the proportion of patients who might benefit from immunotherapy.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antígeno B7-H1/metabolismo , Imunoterapia , Fatores Imunológicos/uso terapêutico , Biomarcadores
4.
Spectrochim Acta A Mol Biomol Spectrosc ; 286: 122000, 2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36279798

RESUMO

Breast cancer is common in women, and its number of patients ranks first among female malignant tumors. Breast cancer is highly heterogeneous, and different types of breast cancer have different biological behaviors and prognoses. Therefore, identifying the different types of breast cancer is of great help in formulating individualized treatment plans. Based on serum Raman spectroscopy and deep learning algorithms, we propose a fast and low-cost diagnosis method for screening triple-negative breast cancer, human epidermal growth factor receptor 2 (HER2)-positive breast cancer, and healthy controls. We collected 75 serum samples in this study, including 23 triple-negative breast cancers, 22 HER2-positive breast cancers, and 30 healthy controls. Using the preprocessed Raman spectra as the input of deep learning, three deep learning models, neural network language model (NNLM), bidirectional long-short-term memory network (BiLSTM), and convolutional neural network (CNN), were established, and the accuracy rates of the three models were 87.78%, 90.37%, and 91.11%, respectively. The experimental results demonstrate the feasibility of serum Raman spectroscopy combined with deep learning algorithms to diagnose breast cancer, which can be used as an effective auxiliary diagnosis method for breast cancer.


Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Feminino , Humanos , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias da Mama/metabolismo , Análise Espectral Raman , Redes Neurais de Computação , Algoritmos
5.
Gene ; 851: 146969, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36261089

RESUMO

BACKGROUND: We previously reported on the association between ESR1 and ESR2 gene variants and heightened risk of breast cancer (BC). Here we investigated the association of common ESR1 and ESR2 gene variants with triple negative BC (TNBC). METHODS: This retrospective case-control study involved 488 BC patients (130 TNBC, 358 non-TNBC patients). ESR1 (rs2234693, rs9340799, rs3020314, rs3798577) and ESR2 (rs928554, rs944459, rs4986938, rs1256049, rs1256030, rs1271572) genotyping was done by real-time PCR. RESULTS: While minor allele frequencies (MAF) of ESR1 variants were comparable between TNBC and non-TNBC subjects, significantly higher ESR2 rs1256049 MAF was seen in TNBC patients. Significantly higher frequency of ESR1 rs3798577 T/C and C/C genotypes were noted in TNBC cases, and significant differences were seen in ESR2 rs928554, rs1256049, and rs1271572 genotype distribution. Increased TNBC risk was associated with ESR1 rs3798577 T/C and C/C genotypes according to codominant and dominant models, while positive association of ESR2 rs928554 with TNBC was seen according to codominant and recessive models, and positive association of ESR2 rs1256049 with TNBC was seen according to codominant and dominant models. Positive interactions were noted between ESR2 rs1271572-ESR1 rs3020314, ESR2 rs1271572-ESR1 rs9340799, and ESR2 rs1271572-ESR1 rs2234693, ESR2 rs4986938-ESR1 rs2234693, and ESR2 rs928554-ESR1 rs9340799. Haplotype analysis confirmed the positive association of ESR1 CATT with TNBC, while ACGGCTC and ACGGTT ESR2 haplotypes were positively associated with TNBC. CONCLUSION: Results of this study confirmed the association of unique ESR1 and ESR2 genetic variants with altered risk of TNBC. This suggests possible diagnostic and prognostic role of these variants with TNBC independent of their association with BC.


Assuntos
Receptor alfa de Estrogênio , Receptor beta de Estrogênio , Neoplasias de Mama Triplo Negativas , Humanos , Estudos de Casos e Controles , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Predisposição Genética para Doença , Genótipo , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/genética , Feminino
6.
Clin Imaging ; 93: 75-82, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36413877

RESUMO

PURPOSE: To assess differences in the mammographic and sonographic appearance of breast cancer in African American (AA) and Non-Latina White (NLW) women. METHODS: We identified AA and NLW women with biopsy proven ductal carcinoma in situ or invasive breast cancer between June 1, 2015 and May 31, 2018. Racial differences in Breast Imaging and Reporting Data System (BI-RADS) imaging features were analyzed by imaging cohorts, i.e. screen detected vs. clinical presentation, using logistic regression adjusted for histology and molecular subtypes. RESULTS: We analyzed 270 AA women with 278 cancers (166 screen detected, 112 clinical) and 586 NLW women with 599 cancers (397 screen detected, 202 clinical). Compared with NLW women, AA women had higher rates of non-dense breast composition (almost entirely fatty 12.0% vs. 4.6%, scattered fibroglandular 50.9% vs. 45.2%; overall P < 0001) in both cohorts and were less likely to have screen detected architectural distortion, (odds ratio (OR) = 0.38, 95% CI 0.18-0.80). AA women were less likely than NLW women to have screen detected irregular than oval/round masses (mammography: OR = 0.36, 95% CI 0.19-0.68; sonography: OR = 0.48, 95% CI 0.24-0.94), and more likely to present clinically with high density masses (OR = 3.03, 95% CI 1.12-8.20) demonstrating posterior enhancement (OR = 3.02, 95% CI 1.11-8.27). CONCLUSION: There are racial differences in the mammographic and sonographic appearance of breast cancer even after accounting for higher rates of triple negative breast cancer in AA women. Understanding these differences may provide breast imagers with a framework to approach breast cancer diagnosis in the AA population in clinical practice.


Assuntos
Afro-Americanos , Neoplasias de Mama Triplo Negativas , Feminino , Humanos , Brancos , Mamografia , Densidade da Mama
7.
Gene ; 851: 147022, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36347335

RESUMO

The response to psychological stress can differ depending on the type and duration of the stressor. Acute stress can facilitate a "fight or flight response" and aid survival, whereas chronic long-term stress with the persistent release of stress hormones such as cortisol has been shown to be detrimental to health. We are now beginning to understand how this stress hormone response impacts important processes such as DNA repair and cell proliferation processes in breast cancer. However, it is not known what epigenetic changes stress hormones induce in breast cancer. Epigenetic mechanisms include modification of DNA and histones within chromatin that may be involved in governing the transcriptional processes in cancer cells in response to changes by endogenous stress hormones. The contribution of endogenous acute or long-term exposure of glucocorticoid stress hormones, and exogenous glucocorticoids to methylation patterns in breast cancer tissues with different aetiologies remains to be evaluated. In vitro and in vivo models were developed to investigate the epigenetic modifications and their contribution to breast cancer progression and aetiology. A panel of triple negative breast cancer cell lines were treated with the glucocorticoid, cortisol which resulted in epigenetic alteration characterised by loss of methylation on promoter regions of tumour suppressor genes including ESR1, and loss of methylation on LINE-1 repetitive element used as a surrogate marker for global methylation. This was verified in vivo in MDA-MB-231 xenografts; the model verified the loss of methylation on ESR1 promoter, and subsequent increase in ESR1 expression in primary tumours in mice subjected to restraint stress. Our study highlights that DNA methylation landscape in breast cancer can be altered in response to stress and glucocorticoid treatment.


Assuntos
Receptor alfa de Estrogênio , Neoplasias de Mama Triplo Negativas , Humanos , Camundongos , Animais , Fulvestranto , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Glucocorticoides/farmacologia , Hidrocortisona/farmacologia , Metilação de DNA
8.
Surg Clin North Am ; 103(1): 201-217, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36410351

RESUMO

The indications for preoperative/neoadjuvant systemic therapy in breast cancer have changed over the past few years. In this article, the authors review the current data for use of neoadjuvant therapy in inoperable and operable settings. The evolution of various neoadjuvant regimens used in triple-negative breast cancer, human epidermal growth factor receptor 2 (HER2) overexpressing/gene-amplified (HER2+) tumors, and hormone receptor positive breast cancer is discussed as well as the role of neoadjuvant chemotherapy in tailoring adjuvant treatment.


Assuntos
Terapia Neoadjuvante , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/cirurgia , Imunoterapia
9.
Drug Dev Res ; 83(1): 208-216, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34347904

RESUMO

Breast cancer (BC), which is widely considered as the most common cancer in women around the world, evokes ~1.7 million new BC cases and 522,000 BC-related deaths each year. Triple negative breast cancer (TNBC) is clinically confirmed as one of the most aggressive subtypes of BC. ORY-1001, a clinically used lysine specific demethylase 1 (LSD1/KDM1A) inhibitor, was investigated herein to confirm its role in the progression of TNBC and reveal the potential mechanism. After treatment with ORY-1001 in MDA-MB-231 and BT549 cells, the cell proliferation and apoptosis were respectively measured by CCK-8 and TUNEL assays. The expression of proliferation- and apoptosis-associated proteins was tested by means of western blot analysis. Then, R1881, an androgen receptor (AR) agonist, was used to evaluate whether the effects of ORY-1001 on proliferation and apoptosis of TNBC cells was mediated by regulating AR. Results indicated that ORY-1001 treatment restrained the proliferation while enhanced the apoptosis of BC cells, accompanied by the change of proliferation- and apoptosis-related proteins expression. Furthermore, ORY-1001 reduced the level of AR in BC cells. After the activation of AR by R1881, the decreased proliferation and enhanced apoptosis of BC cells triggered by ORY-1001 intervention were partially abolished. In conclusion, this paper has presented the first evidence to suggest that ORY-1001 inhibits proliferation and promotes apoptosis of TNBC cells by suppressing AR expression, which may constitute the theoretical basis for the clinical use of ORY-1001 in the treatment of this disease.


Assuntos
Neoplasias de Mama Triplo Negativas , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Histona Desmetilases/farmacologia , Humanos , Receptores Androgênicos/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo
10.
Genome Biol ; 23(1): 248, 2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36451239

RESUMO

We present SIEVE, a statistical method for the joint inference of somatic variants and cell phylogeny under the finite-sites assumption from single-cell DNA sequencing. SIEVE leverages raw read counts for all nucleotides and corrects the acquisition bias of branch lengths. In our simulations, SIEVE outperforms other methods in phylogenetic reconstruction and variant calling accuracy, especially in the inference of homozygous variants. Applying SIEVE to three datasets, one for triple-negative breast (TNBC), and two for colorectal cancer (CRC), we find that double mutant genotypes are rare in CRC but unexpectedly frequent in the TNBC samples.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Filogenia , Sequência de Bases , Análise de Sequência de DNA , DNA , Nucleotídeos
11.
Theranostics ; 12(18): 7646-7667, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36451861

RESUMO

Rationale: High mortality in pancreatic cancer (PDAC) and triple negative breast cancer (TNBC) highlight the need to capitalize on nanoscale-design advantages for multifunctional diagnostics and therapies. DNA/RNA-therapies can provide potential breakthroughs, however, to date, there is no FDA-approved systemic delivery system to solid tumors. Methods: Here, we report a Janus-nanoparticle (jNP)-system with modular targeting, payload-delivery, and targeted-imaging capabilities. Our jNP-system consists of 10 nm ultrasmall superparamagnetic iron oxide nanoparticles (USPION) with opposing antibody-targeting and DNA/RNA payload-protecting faces, directionally self-assembled with commercially available zwitterionic microbubbles (MBs) and DNA/RNA payloads. Results: Sonoporation of targeted jNP-payload-MBs delivers functional reporter-DNA imparting tumor-fluorescence, and micro-RNA126 reducing non-druggable KRAS in PDAC-Panc1 and TNBC-MB231 xenografted tumors. The targeting jNP-system enhances ultrasound-imaging of intra-tumoral microvasculature using less MBs/body weight (BW). The jNP-design enhances USPION's T2*-magnetic resonance (MR) and MR-imaging of PDAC-peritoneal metastases using less Fe/BW. Conclusion: Altogether, data advance the asymmetric jNP-design as a potential theranostic Janus-USPION Modular Platform - a JUMP forward.


Assuntos
MicroRNAs , Neoplasias de Mama Triplo Negativas , Humanos , Medicina de Precisão , Neoplasias de Mama Triplo Negativas/diagnóstico por imagem , Neoplasias de Mama Triplo Negativas/terapia , Diagnóstico por Imagem , DNA
12.
Dis Markers ; 2022: 8446857, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36452344

RESUMO

Objective: Triple negative breast cancer (TNBC) is a kind of cancer that endangers the lives of women all over the world in the 21st century. Heat shock protein member 8 (HSPA8) is the chaperone gene of the heat shock protein family. It is involved in many cellular functions. For example, it promotes the circulation between ATP and ADP, participates in protein folding, and can change the vitality of the cell and inhibit its growth. However, the abnormal expression of HSPA8 gene in TNBC and its diagnostic and prognostic significance still need to be further studied. Methods: First, we used related databases (such as TCGA, GEO, GTEx, ONCOMINE, TIMER2.0, UALCAN, HPA, STRING, CCLE, and Kaplan-Meier plotter databases) to analyze the relationship between HSPA8 and TNBC by bioinformatics. Then, the analysis using only a small part of the experimental work is used to explain our findings. For example, HSPA8 protein expression was evaluated by immunohistochemical method in TNBC tissues. Western blotting experiments were carried out to verify the results. Then, the clinicopathological characteristics of patients with TNBC were analyzed by R software and Cox regression analysis. On the basis, a nomogram is constructed to estimate the 1-, 3-, and 5-year overall survival (OS). The prognostic nomogram performance was calibrated and evaluated by the calibration curve and receiver operating characteristic (ROC) curve. Results: In the study, we analyzed the three GEO databases (including GSE86945, GSE106977, and GSE102088) and found that HSPA8 is one of the central genes of TNBC. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) researches indicated that HSPA8 was mainly involved in partner-mediated autophagy, mRNA catabolism, neutrophil activation, immune response, protein targeting, RNA splicing, RNA catabolism, and other biological processes. Next, we used bioinformatics technology to find that the expression level of HSPA8 in breast cancer (BC) and TNBC samples was significantly higher than that in normal breast tissues, which was determined by analyzing hospital patient samples and related experiments. In addition, the expression level of HSPA8 in BC and TNBC samples was significantly correlated with clinical indexes such as TNM stage. The Cox analysis revealed that the expression of HSPA8 in TNBC had significant clinical prognostic value. The results of nomogram and ROC test show that HSPA8 has significant predictive ability in TNBC. The results of immune infiltration of HSPA8 through the TIMER2.0 database showed that there was a significant correlation between HSPA8 and immune cell subsets. Conclusions: Our results show that the expression of HSPA8 in TNBC has important clinical diagnostic significance and clarify the potential molecular mechanism that promotes the evolution of TNBC. The high expression of HSPA8 may be related with the poor clinical outcome of TNBC. This helps to provide us with a new direction of TNBC targeted therapy.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Neoplasias de Mama Triplo Negativas/genética , Prognóstico , Biomarcadores , Nomogramas , Proteínas de Choque Térmico , Proteínas de Choque Térmico HSC70
13.
Cancer Prev Res (Phila) ; 15(12): 787-789, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36453053

RESUMO

Tamoxifen, the prototypic medication for breast cancer prevention, was approved for this purpose by the FDA in 1998. Other drugs have been proven to be effective in the ensuing decades. But the two major limitations of these have become clear over time: a lack of protection against hormone receptor-negative breast cancer, and a profile of safety and tolerability that is unacceptable to the majority of women at increased breast cancer risk. Recent preclinical data on targeting of the key oncogenic pathway of PI3K/AKT/mTOR signaling with drugs such as rapamycin and everolimus are provocative. Their efficacy signal should be pursued with further research, but their safety and tolerability profiles remain a concern. See related article by Mazumdar et al., p. 791.


Assuntos
Everolimo , Neoplasias de Mama Triplo Negativas , Feminino , Humanos , Everolimo/uso terapêutico , Receptores de Estrogênio , Fosfatidilinositol 3-Quinases , Serina-Treonina Quinases TOR
14.
Cancer Discov ; 12(11): 2496-2497, 2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36321309

RESUMO

Martini and colleagues performed genetic ancestry estimation on a unique international triple-negative breast cancer (TNBC) study enriched for participants with African ancestry. They identified gene signatures indicative of ancestry in race-associated TNBC and found ancestry-associated immunologic differences that may contribute to racial disparities in breast cancer. See related article by Martini et al., p. 2530 (5).


Assuntos
Neoplasias de Mama Triplo Negativas , Feminino , Humanos , Transcriptoma , Imunidade , Biologia
15.
Commun Biol ; 5(1): 1178, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36369329

RESUMO

Cancer cells feature a resting membrane potential (Vm) that is depolarized compared to normal cells, and express active ionic conductances, which factor directly in their pathophysiological behavior. Despite similarities to 'excitable' tissues, relatively little is known about cancer cell Vm dynamics. Here high-throughput, cellular-resolution Vm imaging reveals that Vm fluctuates dynamically in several breast cancer cell lines compared to non-cancerous MCF-10A cells. We characterize Vm fluctuations of hundreds of human triple-negative breast cancer MDA-MB-231 cells. By quantifying their Dynamic Electrical Signatures (DESs) through an unsupervised machine-learning protocol, we identify four classes ranging from "noisy" to "blinking/waving". The Vm of MDA-MB-231 cells exhibits spontaneous, transient hyperpolarizations inhibited by the voltage-gated sodium channel blocker tetrodotoxin, and by calcium-activated potassium channel inhibitors apamin and iberiotoxin. The Vm of MCF-10A cells is comparatively static, but fluctuations increase following treatment with transforming growth factor-ß1, a canonical inducer of the epithelial-to-mesenchymal transition. These data suggest that the ability to generate Vm fluctuations may be a property of hybrid epithelial-mesenchymal cells or those originated from luminal progenitors.


Assuntos
Transição Epitelial-Mesenquimal , Neoplasias de Mama Triplo Negativas , Humanos , Linhagem Celular Tumoral , Células MCF-7 , Potenciais da Membrana
16.
Commun Biol ; 5(1): 1231, 2022 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-36371461

RESUMO

Cell-cell communication and physical interactions play a vital role in cancer initiation, homeostasis, progression, and immune response. Here, we report a system that combines live capture of different cell types, co-incubation, time-lapse imaging, and gene expression profiling of doublets using a microfluidic integrated fluidic circuit that enables measurement of physical distances between cells and the associated transcriptional profiles due to cell-cell interactions. We track the temporal variations in natural killer-triple-negative breast cancer cell distances and compare them with terminal cellular transcriptome profiles. The results show the time-bound activities of regulatory modules and allude to the existence of transcriptional memory. Our experimental and bioinformatic approaches serve as a proof of concept for interrogating live-cell interactions at doublet resolution. Together, our findings highlight the use of our approach across different cancers and cell types.


Assuntos
Transcriptoma , Neoplasias de Mama Triplo Negativas , Humanos , Microfluídica , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica
17.
Int J Nanomedicine ; 17: 5209-5227, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36388877

RESUMO

Triple-negative breast cancer (TNBC) exhibits high recurrence and mortality rates because of the lack of effective treatment targets. Surgery and traditional chemotherapy are the primary treatment options. Immunotherapy shows high potential for treating various cancers but exhibits limited efficacy against TNBC as a monotherapy. Chemoimmunotherapy has broad prospects for applications for cancer treatment conferred through the synergistic immunomodulatory and anti-tumor effects of chemotherapy and immunotherapeutic strategies. However, improving the efficacy of synergistic therapy and reducing the side effects of multiple drugs remain to be the main challenges in chemoimmunotherapy against TNBC. Nanocarriers can target both cancer and immune cells, promote drug accumulation, and show minimal toxicity, making them ideal delivery systems for chemotherapeutic and immunotherapeutic agents. In this review, we introduce the immunomodulatory effects of chemotherapy and combined mechanisms of chemoimmunotherapy, followed by a summary of nanoparticle-mediated chemoimmunotherapeutic strategies used for treating TNBC. This up-to-date synthesis of relevant findings in the field merits contemplation, while considering avenues of investigation to enable advances in the field.


Assuntos
Nanopartículas , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Imunoterapia
18.
Acta Clin Croat ; 61(1): 30-37, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36398075

RESUMO

The benefit of breast magnetic resonance imaging (MRI) in breast-conserving surgery (BCS) is unclear. Our study compared breast cancer patients with and without preoperative breast MRI and their long-term oncologic outcomes are reported. A total of 1378 BCS cases with early breast cancer between 1996 and 2017 were reviewed. Patients with carcinoma in situ or neoadjuvant treatment or having breast MRI after tumor excision were excluded. Of 1378 patients, 270 (19.5%) had preoperative MRI. There were no significant differences regarding T and N stage and molecular subtypes between the groups. Surgical margins were significantly wider in the breast MRI group. Five-year overall survival (OS) was 96.9% in the MRI group and 94.3% in the control group, and this difference was not significant (p=0.11). Five-year local-regional recurrence-free survival (LRFS) was not significantly different either (98.8% and 96.5%, respectively, p=0.41). When analyses were repeated only for patients with hormone receptor-negative or triple-negative breast cancer, there was still no significant difference in OS, LRFS, or disease-free survival. In conclusion, MRI does not seem necessary in all patients undergoing BCS. New prospective randomized controlled trials are needed to determine appropriate use of preoperative MRI and its effects on oncologic outcomes in early breast cancer patients.


Assuntos
Mastectomia Segmentar , Neoplasias de Mama Triplo Negativas , Humanos , Mastectomia Segmentar/métodos , Estudos Prospectivos , Imageamento por Ressonância Magnética/métodos , Intervalo Livre de Doença
19.
Proc Natl Acad Sci U S A ; 119(46): e2207201119, 2022 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-36343244

RESUMO

The transcription variation, leading to various forms of transcripts and protein diversity, remains largely unexplored in triple-negative breast cancers (TNBCs). Here, we presented a comprehensive analysis of RNA splicing in breast cancer to illustrate the biological function and clinical implications of tumor-specific transcripts (TSTs) arising from these splicing junctions. Aberrant RNA splicing or TSTs were frequently harbored in TNBC and were correlated with a poor outcome. We discovered a tumor-specific splicing variant of macrophage receptor with collagenous structure-TST (MARCO-TST), which was distinguished from myeloid cell-specific wild-type MARCO. MARCO-TST expression was associated with poor outcomes in TNBC patients and could promote tumor progression in vitro and in vivo. Mechanically, MARCO-TST interacted with PLOD2 and enhanced the stability of HIF-1α, which resulted in the metabolic dysregulation of TNBC to form a hypoxic tumor microenvironment. MARCO-TST was initiated from a de novo alternative transcription initiation site that was activated by a superenhancer. Tumors with MARCO-TST expression conferred greater sensitivity to bromodomain and extraterminal protein inhibitors. This treatment strategy was further validated in patient-derived organoids. In conclusion, our results revealed the transcription variation landscape of TNBC, highlighting MARCO-TST as a crucial oncogenic transcript and therapeutic target.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/metabolismo , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Carcinogênese/genética , Splicing de RNA , Proliferação de Células , Microambiente Tumoral
20.
Front Immunol ; 13: 965342, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36389835

RESUMO

Background: Due to lack of enough specific targets and the immunosuppressive tumor microenvironment (TME) of triple-negative breast cancer (TNBC), TNBC patients often cannot benefit from a single treatment option. This study aims to explore the regulatory effects of Compound kushen injection (CKI) plus chemotherapy on the TME of TNBC from a single cell level. Methods: A mouse TNBC model in BALB/c mice was established to evaluate the antitumor efficacy and toxicity of CKI combined with chemotherapy. Flow cytometry was used to observe the influence of CKI on the lymphocyte populations in the tumor bearing mice. Both bulk RNA sequencing (RNA-seq) and single-cell RNA-seq (scRNA-seq) were applied to portray the modulation of CKI combined with chemotherapy on the TME of TNBC mice. Results: CKI significantly enhanced the anticancer activity of chemotherapy in vivo with no obvious side effects. Flow cytometry results revealed a significantly higher activation of CD8+ T lymphocytes in the spleens and tumors of the mice with combination therapy. Bulk RNA-seq indicated that CKI could promote the cytotoxic immune cell infiltrating into tumor tissues. Meanwhile, scRNA-seq further revealed that CKI combined with chemotherapy could enhance the percentage of tumor-infiltrating CD8+ T cells, inhibit tumor-promoting signaling pathways, and promote T cell activation and positive regulation of immune response. In addition, CKI showed obvious anticancer activity against MDA-MB-231 breast tumor cells in vitro. Conclusions: The combination of CKI and chemotherapy might provide a higher efficiency and lower toxicity strategy than a single chemotherapy drug for TNBC. CKI potentiates the anti-TNBC effects of chemotherapy by activating anti-tumor immune response in mice.


Assuntos
Antineoplásicos , Neoplasias de Mama Triplo Negativas , Humanos , Camundongos , Animais , Linfócitos T CD8-Positivos/patologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , RNA , Microambiente Tumoral
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