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1.
Br J Radiol ; 93(1106): 20190742, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31778316

RESUMO

OBJECTIVE: One of the major issues in current radiotherapy (RT) is the normal tissue toxicity. A smart combination of agents within the tumor would allow lowering the RT dose required while minimizing the damage to healthy tissue surrounding the tumor. We chose gold nanoparticles (GNPs) and docetaxel (DTX) as our choice of two radiosensitizing agents. They have a different mechanism of action which could lead to a synergistic effect. Our first goal was to assess the variation in GNP uptake, distribution, and retention in the presence of DTX. Our second goal was to assess the therapeutic results of the triple combination, RT/GNPs/DTX. METHODS: We used HeLa and MDA-MB-231 cells for our study. Cells were incubated with GNPs (0.2 nM) in the absence and presence of DTX (50 nM) for 24 h to determine uptake, distribution, and retention of NPs. For RT experiments, treated cells were given a 2 Gy dose of 6 MV photons using a linear accelerator. RESULTS: Concurrent treatment of DTX and GNPs resulted in over 85% retention of GNPs in tumor cells. DTX treatment also forced GNPs to be closer to the most important target, the nucleus, resulting in a decrease in cell survival and increase in DNA damage with the triple combination of RT/ GNPs/DTX vs RT/DTX. Our experimental therapeutic results were supported by Monte Carlo simulations. CONCLUSION: The ability to not only trap GNPs at clinically feasible doses but also to retain them within the cells could lead to meaningful fractionated treatments in future combined cancer therapy. Furthermore, the suggested triple combination of RT/GNPs/DTX may allow lowering the RT dose to spare surrounding healthy tissue. ADVANCES IN KNOWLEDGE: This is the first study to show intracellular GNP transport disruption by DTX, and its advantage in radiosensitization.


Assuntos
Antineoplásicos/farmacologia , Docetaxel/farmacologia , Ouro/farmacologia , Nanopartículas Metálicas , Radiossensibilizantes/farmacologia , Antineoplásicos/farmacocinética , Transporte Biológico , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Docetaxel/farmacocinética , Sinergismo Farmacológico , Feminino , Ouro/farmacocinética , Células HeLa , Humanos , Radiossensibilizantes/farmacocinética , Neoplasias de Mama Triplo Negativas/radioterapia , Células Tumorais Cultivadas , Neoplasias do Colo do Útero/radioterapia
2.
Asian Pac J Cancer Prev ; 20(12): 3679-3687, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31870109

RESUMO

BACKGROUND: Radioresistance remains a challenge for cancer radiotherapy. The present study aims to investigate the role of TMPRSS4 in triple negative breast cancer (TNBC) cell radiosensitivity. MATERIALS AND METHODS: After transfection of MDA-MD-468 triple negative breast cancer cells line by using the lentivirus vector, the effect of TMPRSS4 down-regulation on TNBC radiosensitivity was evaluated by using cloning assay and CCK-8 assay. The CCK-8 assay was also used for performing cell proliferation analysis. Western blot was carried out to detect the expression of certain proteins related to cell cycle pathways (cyclin D1), cell apoptosis pathways (Bax, Bcl2, and Caspase3), DNA damage and DNA damage repair (TRF2, Ku80 , Ë H2AX) . The cell cycle and cell apoptosis were also investigated using flow cytometer analysis. RESULTS: TMPRSS4 expression was down-regulated in MDA-MB-468 cells which enhanced MDA-MB-468 cells radiosensitivity. TMPRSS4 silencing also improved IR induced cell proliferation ability reduction and promoted cell arrested at G2/M phase mediated by 6 Gy IR associated with cyclin D1 expression inhibition. Moreover, TMPRSS4 inhibition enhanced TNBC apoptosis induced by 6 Gy IR following by over-expression of (Bax, Caspase3) and down-regulation of Bcl2 as the pro-apoptotic and anti-apoptotic proteins, respectively. Otherwise, TMPRSS4 down-regulation increases  DNA damage induced by 6 Gy IR and delays DNA damage repair respectively illustrated by downregulation of TRF2 and permanent increase of Ku80 and Ë H2AX expression at 1 h and 10 h post-IR. CONCLUSION: Down-regulation of TMPRSS4 increases triple negative breast cancer cell radiosensitivity and the use of TMPRSS4 inhibitor can be encouraged for improving radiotherapy effectiveness in TNBC radioresistant patients.


Assuntos
Apoptose/genética , Pontos de Checagem da Fase G2 do Ciclo Celular/genética , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Tolerância a Radiação/genética , Serina Endopeptidases/biossíntese , Serina Endopeptidases/genética , Neoplasias de Mama Triplo Negativas/radioterapia , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/efeitos da radiação , Regulação para Baixo/genética , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/genética , Humanos
3.
Int J Mol Sci ; 20(19)2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591311

RESUMO

Proton therapy offers a distinct physical advantage over conventional X-ray therapy, but its biological advantages remain understudied. In this study, we aimed to identify genetic factors that contribute to proton sensitivity in breast cancer (BC). Therefore, we screened relative biological effectiveness (RBE) of 230 MeV protons, compared to 6 MV X-rays, in ten human BC cell lines, including five triple-negative breast cancer (TNBC) cell lines. Clonogenic survival assays revealed a wide range of proton RBE across the BC cell lines, with one out of ten BC cell lines having an RBE significantly different from the traditional generic RBE of 1.1. An abundance of cyclin D1 was associated with proton RBE. Downregulation of RB1 by siRNA or a CDK4/6 inhibitor increased proton sensitivity but not proton RBE. Instead, the depletion of cyclin D1 increased proton RBE in two TNBC cell lines, including MDA-MB-231 and Hs578T cells. Conversely, overexpression of cyclin D1 decreased the proton RBE in cyclin D1-deficient BT-549 cells. The depletion of cyclin D1 impaired proton-induced RAD51 foci formation in MDA-MB-231 cells. Taken together, this study provides important clues about the cyclin D1-CDK4-RB1 pathway as a potential target for proton beam therapy in TNBC.


Assuntos
Ciclina D1/genética , Tolerância a Radiação , Neoplasias de Mama Triplo Negativas/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos da radiação , Ciclina D1/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Células MCF-7 , Terapia com Prótons , Eficiência Biológica Relativa , Transdução de Sinais/efeitos da radiação , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/radioterapia , Raios X
4.
Int J Radiat Oncol Biol Phys ; 105(3): 471-472, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31540590
5.
EBioMedicine ; 47: 163-169, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31416721

RESUMO

BACKGROUND: Utilizing the linear quadratic model and the radiosensitivity index (RSI), we have derived an expression for the genomically adjusted radiation dose (GARD) to model radiation dose effect. We hypothesize GARD is associated with local recurrence and can be used to optimize individual triple negative breast cancer (TNBC) radiation dose. METHODS: TN patients from two independent datasets were assessed. The first cohort consisted of 58 patients treated at 5 European centers with breast conservation surgery followed by adjuvant radiotherapy (RT). The second dataset consisted of 55 patients treated with adjuvant radiation therapy. FINDINGS: In cohort 1, multivariable analysis revealed that as a dichotomous variable (HR: 2.5 95% CI 1-7.1; p = .05), GARD was associated with local control. This was confirmed in the second independent dataset where GARD was the only significant factor associated with local control (HR: 4.4 95% CI 1.1-29.5; p = .04). We utilized GARD to calculate an individualized radiation dose for each TN patient in cohort 2 by determining the physical dose required to achieve the GARD target value (GARD ≥ 21). While 7% of patients were optimized with a dose of 30 Gy, 91% of patients would be optimized with 70 Gy. INTERPRETATION: GARD is associated with local control following whole breast or post-mastectomy radiotherapy (RT) in TN patients. By modeling RT dose effect with GARD, we demonstrate that no single dose is optimal for all patients and propose the first dose range to optimize RT at an individual patient level in TNBC.


Assuntos
Doses de Radiação , Tolerância a Radiação/genética , Radioterapia Adjuvante , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/radioterapia , Idoso , Biomarcadores Tumorais , Estudos de Coortes , Terapia Combinada , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Radioterapia Adjuvante/métodos , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/mortalidade
6.
Breast Cancer Res Treat ; 178(1): 75-86, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31372790

RESUMO

PURPOSE: Radiotherapy (RT) constitutes an important part of breast cancer treatment. However, triple negative breast cancers (TNBC) exhibit remarkable resistance to most therapies, including RT. Developing new ways to radiosensitize TNBC cells could result in improved patient outcomes. The M2 isoform of pyruvate kinase (PK-M2) is believed to be responsible for the re-wiring of cancer cell metabolism after oxidative stress. The aim of the study was to determine the effect of ionizing radiation (IR) on PK-M2-mediated metabolic changes in TNBC cells, and their survival. In addition, we determine the effect of PK-M2 activators on breast cancer stem cells, a radioresistant subpopulation of breast cancer stem cells. METHODS: Glucose uptake, lactate production, and glutamine consumption were assessed. The cellular localization of PK-M2 was evaluated by western blot and confocal microscopy. The small molecule activator of PK-M2, TEPP46, was used to promote its pyruvate kinase function. Finally, effects on cancer stem cell were evaluated via sphere forming capacity. RESULTS: Exposure of TNBC cells to IR increased their glucose uptake and lactate production. As expected, PK-M2 expression levels also increased, especially in the nucleus, although overall pyruvate kinase activity was decreased. PK-M2 nuclear localization was shown to be associated with breast cancer stem cells, and activation of PK-M2 by TEPP46 depleted this population. CONCLUSIONS: Radiotherapy can induce metabolic changes in TNBC cells, and these changes seem to be mediated, at least in part by PK-M2. Importantly, our results show that activators of PK-M2 can deplete breast cancer stem cells in vitro. This study supports the idea of combining PK-M2 activators with radiation to enhance the effect of radiotherapy in resistant cancers, such as TNBC.


Assuntos
Proteínas de Transporte/metabolismo , Glucose/metabolismo , Ácido Láctico/metabolismo , Proteínas de Membrana/metabolismo , Hormônios Tireóideos/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células-Tronco Neoplásicas/metabolismo , Radiação Ionizante , Neoplasias de Mama Triplo Negativas/radioterapia , Regulação para Cima
7.
Int J Radiat Biol ; 95(11): 1507-1516, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31348739

RESUMO

Purpose: Based on clinical and molecular data, breast cancer is a heterogeneous disease. Breast cancers that have no expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) are defined as triple negative breast cancers (TNBCs); luminal cancers have different expressions of ER, PR and/or HER2. TNBCs are frequently linked with advanced disease, poor prognosis and occurrence in young African women, and about 15% of the cases are associated with germline BRCA1/2 mutations. Since radiotherapy is utilized as a principle treatment in the management of TNBC, we aimed to investigate the chromosomal instability and radiosensitivity of lymphocytes in TNBC patients compared to luminal breast cancer patients and healthy controls using the micronucleus (MN) assay. The effect of mutations in breast cancer susceptibility genes on chromosomal radiosensitivity was also evaluated.Methods: Chromosomal radiosensitivity was evaluated in the G0 (83 patients and 90 controls) and S/G2 (34 patients and 17 controls) phase of the cell cycle by exposing blood samples from all patients and controls to 2 and 4 Gy ionizing radiation (IR).Results: In the G0 MN assay, the combined cohort of all breast cancer, TNBC and luminal patients' exhibit significantly elevated spontaneous MN values compared to controls indicating chromosomal instability. Chromosomal radiosensitivity is also significantly elevated in the combined cohort of all breast cancer patients compared to controls. The TNBC patients, however, do not exhibit enhanced chromosomal radiosensitivity. Similarly, in the S/G2 phase, 76% of TNBC patients do not show enhanced chromosomal radiosensitivity compared to the controls. In both the G0 and S/G2 phase, luminal breast cancer patients demonstrate a shift toward chromosomal radiosensitivity compared to TNBC patients and controls.Conclusions: The observations of the MN assay suggest increased chromosomal instability and chromosomal radiosensitivity in South African breast cancer patients. However, in TNBC patients, the irradiated MN values are not elevated. Our results suggest that the healthy lymphocytes in TNBC patients could handle higher doses of IR.


Assuntos
Instabilidade Cromossômica , Cromossomos/efeitos da radiação , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/radioterapia , Adulto , Proteína BRCA1/genética , Estudos de Casos e Controles , Ciclo Celular , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Testes para Micronúcleos , Pessoa de Meia-Idade , Mutação , Tolerância a Radiação , Radiação Ionizante
8.
Br J Radiol ; 92(1100): 20190283, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31219711

RESUMO

OBJECTIVE: The incorporation of high atomic number materials such as gold nanoparticles (GNPs) into tumor cells is being tested to enhance the local radiotherapy (RT) dose. It is also known that the radiosensitivity of tumor cells depends on the phase of their cell cycle. Triple combination of GNPs, phase of tumor cell population, and RT for improved outcomes in cancer treatment. METHODS: We used a double-thymidine block method for synchronization of the tumor cell population. GNPs of diameters 17 and 46 nm were used to capture the size dependent effects. A radiation dose of 2 Gy with 6 MV linear accelerator was used to assess the efficacy of this proposed combined treatment. A triple negative breast cancer cell line, MDA-MB-231 was chosen as the model cell line. Monte Carlo (MC) calculations were done to predict the GNP-mediated cell death using the experimental GNP uptake data. RESULTS: There was a 1.5- and 2- fold increase in uptake of 17 and 46 nm GNPs in the synchronized cell population, respectively. A radiation dose of 2 Gy with clinically relevant 6 MV photons resulted in a 62 and 38 % enhancement in cell death in the synchronized cell population with the incorporation of 17 and 46 nm GNPs, respectively. MC data supported the experimental data, but to a lesser extent. CONCLUSION: A triple combination of GNPs, cell cycle synchronization, and RT could pave the way to enhance the local radiation dose while minimizing side effects to the surrounding healthy tissue. ADVANCES IN KNOWLEDGE: This is the first study to show that the combined use of GNPs, phase of tumor cell population, and RT could enhance tumor cell death.


Assuntos
Ouro/farmacologia , Radiossensibilizantes/farmacologia , Neoplasias de Mama Triplo Negativas/radioterapia , Feminino , Humanos , Nanopartículas Metálicas , Dosagem Radioterapêutica , Células Tumorais Cultivadas
9.
Int J Radiat Oncol Biol Phys ; 105(2): 267-274, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31175905

RESUMO

PURPOSE: To report 5-year outcomes of a phase 2 trial of hypofractionated whole breast irradiation (HF-WBI) completed in 3 weeks, inclusive of a sequential boost. METHODS AND MATERIALS: Women with stage 0-IIIA breast cancer (ductal carcinoma in situ through T2N2a) were enrolled on a prospective, phase 2 trial of accelerated HF-WBI. We delivered a whole breast dose of 36.63 Gy in 11 fractions of 3.33 Gy, with an equivalent dose to the regional nodes when indicated, followed by a tumor bed boost of 13.32 Gy in 4 fractions of 3.33 Gy over a total of 15 treatment days. The primary endpoint was locoregional control; secondary endpoints included acute/late toxicity and physician-assessed and patient-reported breast cosmesis. RESULTS: Between 2009 and 2017, we enrolled 150 patients, of whom 146 received the protocol treatment. Median age was 54 years (range, 33-82) and median follow-up was 62 months. Patients with higher-risk disease comprised 59% of the cohort, including features such as young age (33% ≤50 years), positive nodes (13%), triple-negative disease (11%), and treatment with regional nodal irradiation (11%) and/or neoadjuvant/adjuvant chemotherapy (36%). Five-year estimated locoregional and distant control were 97.7% (95% confidence interval [CI], 93.0%-99.3%) and 97.9% (95% CI, 93.6%-99.3%), respectively. Five-year breast cancer-specific and overall survival were 99.2% (95% CI, 94.6%-99.9%) and 97.3% (95% CI, 91.9%-99.1%), respectively. Acute/late grade 2 and 3 toxicities were observed in 30%/10% and 1%/3% of patients, respectively. There were no grade 4 or 5 toxicities. Physicians assessed breast cosmesis as good or excellent in 95% of patients; 85% of patients self-reported slight to no difference between the treated and untreated breast. CONCLUSIONS: Our phase 2 trial offers one of the shortest courses of HF-WBI; at 5 years of follow-up there continues to be excellent locoregional control and low toxicity with favorable cosmetic outcomes in a heterogeneous cohort of patients.


Assuntos
Neoplasias da Mama/radioterapia , Carcinoma Intraductal não Infiltrante/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/tratamento farmacológico , Carcinoma Intraductal não Infiltrante/patologia , Quimioterapia Adjuvante , Intervalos de Confiança , Feminino , Humanos , Modelos Lineares , Irradiação Linfática , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Estudos Prospectivos , Hipofracionamento da Dose de Radiação , Radiodermatite/etiologia , Planejamento da Radioterapia Assistida por Computador , Radioterapia Conformacional/efeitos adversos , Reirradiação , Fatores de Tempo , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/radioterapia
10.
Cancer Genomics Proteomics ; 16(4): 257-266, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31243106

RESUMO

BACKGROUND/AIM: Radiation therapy (RT) represents a therapeutic option in breast cancer (BC). Even if a great number of BC patients receive RT, not all of them report benefits, due to radioresistance that gets activated through several factors, such as the hormone receptor status. Herein, we analyzed the gene expression profiles (GEP) induced by RT in triple-negative BC (TNBC) MDA-MB-231, to study signalling networks involved in radioresistance. MATERIALS AND METHODS: GEP of MDA-MB-231 BC cells treated with a high dose of radiation, went through cDNA microarray analysis. In addition, to examine the cellular effects induced by RT, analyses of morphology and clonogenic evaluation were also conducted. RESULTS: A descriptive report of GEP and pathways induced by IR is reported from our microarray data. Moreover, the MDA-MB-231 Radioresistent Cell Fraction (RCF) selected, included specific molecules able to drive radioresistance. CONCLUSION: In summary, our data highlight, the RT response of TNBC MDA-MB-231 cell line at a transcriptional level, in terms of activating radioresistance in these cells, as a model of late-stage BC.


Assuntos
Radiação Ionizante , Transcriptoma/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/radioterapia , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias de Mama Triplo Negativas/patologia
11.
Int J Radiat Oncol Biol Phys ; 105(1): 174-182, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31085287

RESUMO

PURPOSE: Use of adjuvant radiation therapy (RT) after neoadjuvant chemotherapy (NAC) in node-positive breast cancer (BC) is highly variable. In ACOSOG Z1071, RT after NAC was used at the discretion of treating physicians. Herein, we report the impact of RT and pathologic response on locoregional recurrence (LRR) after NAC. METHODS AND MATERIALS: ACOSOG Z1071 enrolled women with cT0-4N1-2 BC treated with NAC from 2009 to 2011. Patients underwent sentinel node surgery and completion axillary lymph node dissection. The RT was at the discretion of the treating physicians. Patient outcomes were analyzed as a function of clinical-pathologic factors and use of RT. RESULTS: Of 701 eligible patients, mastectomy was performed in 423 (59.6%) and breast-conserving surgery in 277 (40.4%). After NAC, residual disease was observed in 506 (72.2%), and 195 (27.8%) had a pathologic complete response. Of the patients, 591 (85.3%) received adjuvant RT and 102 (14.7%) did not. Median follow-up was 5.9 years. Forty-three patients (6.1%) experienced LRR, 145 (20.7%) experienced distant metastasis, and 142 (20.4%) died. Patients with pathologic complete response had the best LRR-relapse-free survival (hazard ratio [HR], 0.32; 95% confidence interval, 0.12-0.81; P = .016), distant metastasis-free survival (HR, 0.31; 95% CI, 0.19-0.52; P < .0001), BC-specific survival (HR, 0.34; 95% CI, 0.19-0.59; P = .0001) and overall survival (HR, 0.39; 95% CI, 0.240-0.63; P = .001) compared to patients with residual disease after NAC. Patients with triple-negative BC had a higher LRR rate compared to those with hormone receptor-positive BC (HR, 5.91; 95% CI, 2.80-12.49). There was a trend toward lower LRR with the use of postmastectomy and regional nodal RT, but there was no impact on overall, disease-free, or BC-specific survival. CONCLUSION: In the ACOSOG Z1071 trial, in which the use of RT after NAC was at the discretion of the treating physicians, RT was associated with a trend toward decreased LRR. There was no association of RT with overall survival, BC-specific survival, or Disease Specific Survival. Triple-negative BC was associated with higher locoregional relapse rates.


Assuntos
Neoplasias da Mama/radioterapia , Excisão de Linfonodo , Terapia Neoadjuvante , Recidiva Local de Neoplasia , Axila , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Quimioterapia Adjuvante/métodos , Intervalos de Confiança , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Irradiação Linfática , Mastectomia/estatística & dados numéricos , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/prevenção & controle , Neoplasia Residual , Estudos Prospectivos , Radioterapia Adjuvante/estatística & dados numéricos , Biópsia de Linfonodo Sentinela , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/radioterapia , Neoplasias de Mama Triplo Negativas/terapia
12.
Biomolecules ; 9(5)2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31058868

RESUMO

Aberrant activation of signal transducer and activator of transcription 3 (STAT3) has been documented in various malignancies including triple-negative breast cancers (TNBCs). The STAT3 transcription factor can regulate the different important hallmarks of tumor cells, and thus, targeting it can be a potential strategy for treating TNBC, for which only limited therapeutic options are available. In this study, we analyzed the possible effect of (-)-galiellalactone and its novel analogues, SG-1709 and SG-1721, and determined whether these agents exerted their antineoplastic effects by suppressing the STAT3 signaling pathway in TNBC cells. The two analogues, SG-1709 and SG-1721, inhibited both constitutive as well as inducible STAT3 phosphorylation at tyrosine 705 more effectively than (-)-galiellalactone, which indicates that the analogues are more potent STAT3 blockers. Moreover, SG-1721 not only inhibited nuclear translocation and DNA binding of STAT3 but also induced apoptosis, and decreased expression of diverse oncogenic proteins. Interestingly, SG-1721 also exhibited an enhanced apoptotic effect when combined with radiotherapy. Furthermore, in vivo administration of SG-1721 significantly attenuated breast xenograft tumor growth via decreasing levels of p-STAT3. Therefore, SG-1721 may be a promising candidate for further application as a pharmacological agent that can target STAT3 protein in treating TNBC.


Assuntos
Apoptose/efeitos dos fármacos , Lactonas/farmacologia , Fator de Transcrição STAT3/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Animais , Biomarcadores Tumorais/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Janus Quinases/metabolismo , Lactonas/química , Camundongos Nus , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/radioterapia
13.
Plast Reconstr Surg ; 143(6): 1666-1676, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30907808

RESUMO

BACKGROUND: Radiotherapy plays an essential role in the oncologic management of breast cancer. However, patients who undergo radiotherapy experience significantly more wound complications during the reconstructive process. Deferoxamine has immense potential to up-regulate angiogenesis and improve reconstructive outcomes. The purpose of this study was to determine the impact of deferoxamine on breast cancer cell proliferation in vitro, to delineate oncologic safety concerns regarding the use of deferoxamine as a regenerative therapeutic. METHODS: The dose-dependent effect of radiation and deferoxamine on two triple-negative breast cancer cell lines (MDA-MB-231 and MDA-MB-468) was determined by means of MTS (percentage cell viability) and tumorsphere (sphere number) analysis. Radiation therapy and deferoxamine were delivered both individually and in combination, and all experiments were completed in triplicate. Intracellular iron, nuclear factor-κB localization, and apoptosis/necrosis assays were performed to delineate mechanism. Analysis of variance statistical analysis was performed using SPSS (p < 0.05). RESULTS: For both cell lines, percentage viability and sphere number significantly decreased following exposure to 10 Gy of radiation. Surprisingly, the administration of 25 µM deferoxamine also significantly decreased each metric. The administration of deferoxamine (100 µM) in combination with radiation (10 Gy) resulted in significantly reduced percentage viability and sphere number compared with the administration of radiation alone. Deferoxamine treatment decreased intracellular iron, suppressed nuclear factor-κB activation, and induced apoptosis. CONCLUSION: Radiation and deferoxamine significantly decrease breast cancer proliferation when delivered independently and in combination, suggesting deferoxamine may be safely used to facilitate improved reconstructive outcomes among triple-negative breast cancer survivors. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desferroxamina/farmacologia , Ferro/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Análise de Variância , Apoptose/efeitos da radiação , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos da radiação , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta à Radiação , Feminino , Humanos , Imageamento Tridimensional , Doses de Radiação , Sensibilidade e Especificidade , Neoplasias de Mama Triplo Negativas/radioterapia
14.
Biosci Rep ; 39(3)2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30842344

RESUMO

BACKGROUND: Radiotherapy is an important locoregional treatment, and its effect on triple-negative breast cancer (TNBC) needs to be enhanced. The aim of the present study was to investigate the potential effects of XRCC4 on radiosensitivity of TNBC. METHODS: The RNAi technique was implemented to establish the TNBC stable cell line with XRCC4 knockdown. MTT assay was used to detect the effect of XRCC4 knockdown on cell proliferation. Western blot and immunohistochemistry assays were employed to identify protein expression. Colony assay was performed to detect the effect of XRCC4 knockdown on the colony formation ability of TNBC cells with radiation treatment. Comet assay was conducted to evaluate the influence of XRCC4 silencing on DNA repair activity in ionizing radiation. In addition, we performed a survival analysis based on data in TCGA database. RESULTS: XRCC4 knockdown by lentivirus-mediated shRNA had no significant effect on proliferation of TNBC cells. Knockdown of XRCC4 could substantially increase the sensitivity of TNBC cells to ionizing radiation. The DNA damage level was detected to be increased in the XRCC4 knockdown group, indicating there was a significant repair delay in the XRCC4-deleted cells. Clinical sample analysis exhibited that there were various XRCC4 expression in different patients with TNBC. Moreover, survival analysis showed that high expression of XRCC4 was significantly associated with poor progression-free survival after radiotherapy in TNBC patients. Conclusion: Our findings suggest that XRCC4 knockdown sensitizes TNBC cells to ionizing radiation, and could be considered as a novel predictor of radiosensitivity and a promising target for TNBC.


Assuntos
Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Interferência de RNA , Tolerância a Radiação/genética , Radiação Ionizante , Neoplasias de Mama Triplo Negativas/radioterapia , Adulto , Idoso , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/efeitos da radiação , Ensaio Cometa , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Reparo do DNA/efeitos da radiação , Feminino , Humanos , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
15.
Radiother Oncol ; 132: 48-54, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30825969

RESUMO

PURPOSE: The use of post-mastectomy radiation therapy (PMRT) for patients with node-negative, triple negative breast cancer (TNBC) is controversial. This study of a large, contemporary US database described national practice patterns and addressed the impact of PMRT on survival for patients with node-negative TNBC. METHODS: The National Cancer Data Base was queried (2004-2014) for women with non-metastatic TNBC with pT1-4N0M0 disease undergoing mastectomy. Use of PMRT was assessed. Multivariable logistic regression ascertained factors associated with PMRT use. The Kaplan-Meier analysis evaluated overall survival (OS) between patients managed with either PMRT or observation following mastectomy when stratifying by pT stage. Cox proportional hazards modeling determined variables associated with OS. RESULTS: A total of 14,464 patients met the selection criteria; of these, 1,569 (10.8%) received PMRT, whereas 12,895 (89.2%) did not receive PMRT. Use of PMRT varied significantly with pT stage, with only 5.7% of T1 patients undergoing PMRT, while 51.6% of patients with T3 disease underwent PMRT. Use of PMRT was associated with superior OS for patients with pT3 disease but not for patients with other T stages. Greater age was associated with decreased likelihood of PMRT use, while increased T stage and positive surgical margins were associated with use of PMRT. On multivariate analysis, increased age, T stage, and positive surgical margins were associated with worse OS. CONCLUSIONS: In the largest study to date evaluating the use of PMRT in patients with node-negative TNBC, the use of PMRT was low in patients with T1 and T2 disease. Additionally, while an OS benefit was observed with the use of PMRT in patients with T3 disease, there was no benefit with the use of PMRT in other T stage groups. Further prospective studies are recommended to further elucidate the benefit on PMRT in patients with node-negative TNBC.


Assuntos
Neoplasias de Mama Triplo Negativas/radioterapia , Idoso , Bases de Dados Factuais , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfonodos/patologia , Metástase Linfática , Mastectomia/estatística & dados numéricos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Prospectivos , Radioterapia Adjuvante/estatística & dados numéricos , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/cirurgia , Estados Unidos/epidemiologia
16.
Breast Cancer Res Treat ; 175(2): 473-478, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30796656

RESUMO

PURPOSE: We sought to identify trends over time with respect to the use of hypofractionated whole breast irradiation (HF-WBI) in women with triple negative breast cancer (TNBC) in the national cancer database (NCDB). METHODS: Trends in utilization of HF-WBI in women diagnosed with T1-2N0 TNBC in the NCDB between 2008 and 2013 were analyzed. Case-matched luminal A women were used for comparison. Variables included age, race, year of diagnosis, insurance status, income quartile, receipt of neoadjuvant chemotherapy, and institution (academic vs. community). Chi square, logistic regression, and multivariate analysis was performed. RESULTS: Utilization of HF-WBI among the 53,269 TNBC women identified steadily increased from 4.7% in 2008 to 14.0% in 2013 for women with TNBC compared to luminal A cancer whose utilization increased from 7.3 to 23.3% over the same time frame (p < 0.001). On univariate analysis, HF-WBI was associated with increasing age (p < 0.001), Medicare insurance (p < 0.001), race (p = 0.041), diagnosis after 2011 (p < 0.001), higher income quartile (p < 0.001), and treatment at academic institutions (p < 0.001). On multivariate analysis, age (p < 0.001, OR 1.038 per year), income quartile (p = 0.002, OR 1.061 per increase in quartile), treatment at an academic institution (p < 0.001, OR 1.78) significantly increased use of HF-WBI. CONCLUSIONS: Treatment at an academic center and year of diagnosis were most correlated with increased HF-WBI in T1-2N0 TNBC women in the NCDB from 2008 to 2013, followed by increasing age and income. Only 14% of T1-2N0 TNBC women received HF-WBI in 2013. Focus on increased utilization is needed for non-academic centers, lower income, and younger women.


Assuntos
Mama/efeitos da radiação , Hipofracionamento da Dose de Radiação , Radioterapia Adjuvante/métodos , Neoplasias de Mama Triplo Negativas/radioterapia , Idoso , Idoso de 80 Anos ou mais , Mama/patologia , Carcinoma Intraductal não Infiltrante , Bases de Dados Factuais , Feminino , Humanos , Mastectomia Segmentar , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/cirurgia
17.
Artigo em Inglês | MEDLINE | ID: mdl-30621221

RESUMO

In this US-based study of the National Cancer Database (NCDB), we examined 8550 patients diagnosed with non-metastatic, invasive inflammatory breast cancer (IBC) who received surgery from 2004⁻2013. Patients were grouped into four biologic subtypes (HR⁺/HER2-, HR⁺/HER2⁺, HR-/HER2⁺, HR-/HER2-). On average, women were 56 years of age at diagnosis and were followed for a median of 3.7 years. The majority were white (80%), had private health insurance (50%), and presented with poorly differentiated tumors (57%). Approximately 46% of the cancers were >5 cm. Most patients underwent mastectomy (94%) and received radiotherapy (71%). Differences by biologic subtypes were observed for grade, lymph node invasion, race, and tumor size (p < 0.0001). Patients experiencing pathologic complete response (pCR, 12%) vs. non-pCR had superior 5-year overall survival (OS) (77% vs. 54%) (p < 0.0001). Survival was poor for triple-negative (TN) tumors (37%) vs. other biologic subtypes (60%) (p < 0.0001). On multivariable analysis, TN-IBC, positive margins, and not receiving either chemotherapy, hormonal therapy or radiotherapy were independently associated with poor 5-year survival (p < 0.0001). In this analysis of IBC, categorized by biologic subtypes, we observed significant differential tumor, patient and treatment characteristics, and OS.


Assuntos
Neoplasias Inflamatórias Mamárias/patologia , Neoplasias de Mama Triplo Negativas/patologia , Feminino , Humanos , Neoplasias Inflamatórias Mamárias/metabolismo , Neoplasias Inflamatórias Mamárias/radioterapia , Neoplasias Inflamatórias Mamárias/cirurgia , Mastectomia , Pessoa de Meia-Idade , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Análise de Sobrevida , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/radioterapia , Neoplasias de Mama Triplo Negativas/cirurgia
18.
Cancer Radiother ; 23(1): 38-45, 2019 Feb.
Artigo em Francês | MEDLINE | ID: mdl-30595340

RESUMO

PURPOSE: The purpose of this study was to evaluate locoregional control and describe the patterns of locoregional failure in women with breast cancer irradiated by a previously described post-mastectomy highly conformal electron beam radiotherapy technique. MATERIAL AND METHODS: We included all women irradiated by post-mastectomy highly conformal electron beam radiotherapy technique for non-metastatic breast cancer between 2007 and 2011 in our department. All cases of bilateral breast cancer were excluded. All patients who experienced locoregional recurrence have been studied. Mapping patterns of regional recurrences was also performed and compared with the European Society for Radiotherapy and Oncology (ESTRO) and Radiotherapy Oncology Group (RTOG) guidelines of volume definition and delineation guidelines. RESULTS: With a median follow-up of 64 months (range: 6-102 months), 5-year locoregional recurrence-free and overall survival probabilities were 90 % (95 % confidence interval [95 %CI]: 88.1-92.4) and 90.9 % (95 %CI: 88.9-93), respectively. Among the 796 patients included in the study, 23 patients (2.9 %) presented locoregional recurrences of them only 13 (1.6%) were presented with local recurrence. The majority of them presented aggressive biological features with grade III tumours in 17 patients (74 %) with high mitotic index in 16 cases (70 %) and triple negative tumours in 12 (52 %). Lymphovascular invasion was observed in 11 cases (48 %). In 14 cases the locoregional recurrences were diagnosed at the same time as the metastatic disease whereas 4 patients presented distant metastases secondarily. Locoregional recurrences occurred in 11 cases "in field" although adequate doses and volumes were used and in 12 cases "outfield", out of irradiated volume. Local recurrences occurred in 13 patients with 12 recurrences within the irradiated volumes. Regional recurrences occurred in 13 patients with 15 lymph nodes metastases identified. Four nodal recurrences occurred outside the ESTRO clinical target volume and within the RTOG clinical target volume and two occurred outside both RTOG and ESTRO clinical target volumes. CONCLUSION: In presented series, the local recurrence resulted mostly from of biologic radio resistance whereas regional recurrences were caused by geographical miss. A number of nodal recurrences could occur outside the target volumes defined by ESTRO and RTOG.


Assuntos
Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Recidiva Local de Neoplasia/patologia , Radioterapia Conformacional/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/mortalidade , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/radioterapia , Carcinoma Lobular/mortalidade , Carcinoma Lobular/patologia , Carcinoma Lobular/radioterapia , Elétrons , Feminino , Seguimentos , Humanos , Metástase Linfática , Mastectomia , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/radioterapia
19.
Cancer Biother Radiopharm ; 34(1): 13-23, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30351218

RESUMO

INTRODUCTION: CLR1404 is a theranostic molecular agent that can be radiolabeled with 124I (CLR 124) for positron emission tomography (PET) imaging, or 131I (CLR 131) for single-photon emission computed tomography (SPECT) imaging and targeted radionuclide therapy. This pilot study evaluated a pretreatment dosimetry methodology in a triple-negative breast cancer patient who was uniquely enrolled in both a CLR 124 PET imaging clinical trial and a CLR 131 therapeutic dose escalation clinical trial. MATERIALS AND METHODS: Three-dimensional PET/CT images were acquired at 1, 3, 24, 48, and 120 h postinjection of 178 MBq CLR 124. One month later, pretherapy 2D whole-body planar images were acquired at 0.25, 5, 24, 48, and 144 h postinjection of 370 MBq CLR 131. Following the therapeutic administration of 1990 MBq CLR 131, 3D SPECT/CT images were acquired at 74, 147, 334, and 505 h postinjection. The therapeutic CLR 131 voxel-level absorbed dose was estimated from PET (RAPID PET) and SPECT (RAPID SPECT) images using a Geant4-based Monte Carlo dosimetry platform called RAPID (Radiopharmaceutical Assessment Platform for Internal Dosimetry), and region of interest (ROI) mean doses were also estimated using the OLINDA/EXM software based on PET (OLINDA PET), SPECT (OLINDA SPECT), and planar (OLINDA planar) images. RESULTS: The RAPID PET and OLINDA PET tracer-predicted ROI mean doses correlated well (m ≥ 0.631, R2 ≥ 0.694, p ≤ 0.01) with both the RAPID SPECT and OLINDA SPECT therapeutic mean doses. The 2D planar images did not have any significant correlations. The ROI mean doses differed by -4% to -43% between RAPID and OLINDA/EXM, and by -19% to 29% between PET and SPECT. The 3D dose distributions and dose volume histograms calculated with RAPID were similar for the PET/CT and SPECT/CT. CONCLUSIONS: This pilot study demonstrated that CLR 124 pretreatment PET images can be used to predict CLR 131 3D therapeutic dosimetry better than CLR 131 2D planar images. In addition, unlike OLINDA/EXM, Monte Carlo dosimetry methods were capable of accurately predicting dose heterogeneity, which is important for predicting dose-response relationships and clinical outcomes.


Assuntos
Imageamento Tridimensional/métodos , Iodobenzenos/administração & dosagem , Éteres Fosfolipídicos/administração & dosagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/administração & dosagem , Planejamento da Radioterapia Assistida por Computador/métodos , Neoplasias de Mama Triplo Negativas/diagnóstico por imagem , Neoplasias de Mama Triplo Negativas/radioterapia , Feminino , Humanos , Projetos Piloto , Estudos Retrospectivos
20.
Int J Radiat Oncol Biol Phys ; 103(1): 195-207, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30196056

RESUMO

PURPOSE: The lack of a molecular target in triple-negative breast cancer (TNBC) makes it one of the most challenging breast cancers to treat. Radiation therapy (RT) is an important treatment modality for managing breast cancer; however, we previously showed that RT can also reprogram a fraction of the surviving breast cancer cells into breast cancer-initiating cells (BCICs), which are thought to contribute to disease recurrence. In this study, we characterize mebendazole (MBZ) as a drug with potential to prevent the occurrence of radiation-induced reprogramming and improve the effect of RT in patients with TNBC. METHODS AND MATERIALS: A high-throughput screen was used to identify drugs that prevented radiation-induced conversion of TNBC cells into cells with a cancer-initiating phenotype and exhibited significant toxicity toward TNBC cells. MBZ was one of the drug hits that fulfilled these criteria. In additional studies, we used BCIC markers and mammosphere-forming assays to investigate the effect of MBZ on the BCIC population. Staining with propidium iodide, annexin-V, and γ-H2AX was used to determine the effect of MBZ on cell cycle, apoptosis, and double-strand breaks. Finally, the potential for MBZ to enhance the effect of RT in TNBC was evaluated in vitro and in vivo. RESULTS: MBZ efficiently depletes the BCIC pool and prevents the ionizing radiation-induced conversion of breast cancer cells into therapy-resistant BCICs. In addition, MBZ arrests cells in the G2/M phase of the cell cycle and causes double-strand breaks and apoptosis. MBZ sensitizes TNBC cells to ionizing radiation in vitro and in vivo, resulting in improved tumor control in a human xenograft model of TNBC. CONCLUSIONS: The data presented in this study support the repurposing of MBZ as a combination treatment with RT in patients with TNBC.


Assuntos
Mebendazol/uso terapêutico , Neoplasias de Mama Triplo Negativas/radioterapia , Animais , Apoptose/efeitos da radiação , Desdiferenciação Celular/efeitos da radiação , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Feminino , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia
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