RESUMO
Triple-negative breast cancer (TNBC) commonly develops resistance to chemotherapy, yet markers predictive of chemoresistance in this disease are lacking. Here, we define WNT10B-dependent biomarkers for ß-CATENIN/HMGA2/EZH2 signaling predictive of reduced relapse-free survival. Concordant expression of HMGA2 and EZH2 proteins is observed in MMTV-Wnt10bLacZ transgenic mice during metastasis, and Hmga2 haploinsufficiency decreased EZH2 protein expression, repressing lung metastasis. A novel autoregulatory loop interdependent on HMGA2 and EZH2 expression is essential for ß-CATENIN/TCF-4/LEF-1 transcription. Mechanistically, both HMGA2 and EZH2 displaced Groucho/TLE1 from TCF-4 and served as gatekeepers for K49 acetylation on ß-CATENIN, which is essential for transcription. In addition, we discovered that HMGA2-EZH2 interacts with the PRC2 complex. Absence of HMGA2 or EZH2 expression or chemical inhibition of Wnt signaling in a chemoresistant patient-derived xenograft (PDX) model of TNBC abolished visceral metastasis, repressing AXIN2, MYC, EZH2, and HMGA2 expression in vivo. Combinatorial therapy of a WNT inhibitor with doxorubicin synergistically activated apoptosis in vitro, resensitized PDX-derived cells to doxorubicin, and repressed lung metastasis in vivo. We propose that targeting the WNT10B biomarker network will provide improved outcomes for TNBC. SIGNIFICANCE: These findings reveal targeting the WNT signaling pathway as a potential therapeutic strategy in triple-negative breast cancer.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/5/982/F1.large.jpg.
Assuntos
Proteínas Proto-Oncogênicas/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Proteínas Wnt/metabolismo , Acetilação , Alelos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Proteína Potenciadora do Homólogo 2 de Zeste/biossíntese , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Proteína HMGA2/biossíntese , Proteína HMGA2/genética , Proteína HMGA2/metabolismo , Humanos , Fator 1 de Ligação ao Facilitador Linfoide , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Metástase Neoplásica , Pirimidinonas/administração & dosagem , Pirimidinonas/farmacologia , Taxa de Sobrevida , Fator de Transcrição 4 , Neoplasias de Mama Triplo Negativas/genética , beta Catenina/metabolismoRESUMO
The Exophiala genus is responsible for many superficial and invasive infections resulting from black fungi. Identification of Exophiala at the species level is based on morphological observations complemented by molecular tests. The aim of this study was to identify 23 clinical isolates of Exophiala spp. and evaluate the antifungal susceptibility to seven different agents. Molecular identification was based on an analysis of ITS region of rDNA using genomic databases. The micromorphology was evaluated by microculture and scanning electron microscopy. The susceptibility tests were performed using the antifungal agents 5-fluorocytosine (5-FC), amphotericin B (AMB), itraconazole (ITC), voriconazole (VRC), posaconazole (PSC), caspofungin (CFG) and terbinafine (TRB). The ITS analysis identified 100% of the following isolates as: E. dermatitidis (8), E. xenobiotica (6), E. bergeri (4), E. oligosperma (3), E. spinifera (1) and E. mesophila (1). The antifungal susceptibility tests showed that the triazoles compounds were in vitro the most active agents against Exophiala. ITS sequencing enabled the accurate identification of the 23 tested isolates. The triazoles, particularly itraconazole and posaconazole, exhibited MIC values lower than AMB, CAS and 5-FC. Although the guidelines do not indicate AMB for treatment against Exophiala spp., this study showed activity for all of the tested species, except E. mesophila.
Assuntos
Antifúngicos/farmacologia , Exophiala/efeitos dos fármacos , Exophiala/genética , Variação Genética , Feoifomicose/microbiologia , Adolescente , Adulto , Idoso , Anfotericina B/farmacologia , Brasil/epidemiologia , Caspofungina , Criança , Pré-Escolar , DNA Espaçador Ribossômico/genética , Equinocandinas/farmacologia , Exophiala/classificação , Exophiala/ultraestrutura , Feminino , Genótipo , Humanos , Itraconazol/farmacologia , Lipopeptídeos/farmacologia , Masculino , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura , Pessoa de Meia-Idade , Feoifomicose/sangue , Feoifomicose/epidemiologia , FenótipoRESUMO
La tercera causa más frecuente de Infecciones Asociadas a la Atención de Salud [IAAS], es la Infección de Herida Operatoria [IHO], correspondiendo al 14% a 16% de todas las infecciones nosocomiales. La mayoría de las IAAS pueden detectarse durante la hospitalización, sin embargo actualmente algunas IHO se presentan cuando los pacientes están en su domicilio y solo se diagnostican cuando vuelven a control. Para su pesquisa se utilizan diversos tipos de vigilancia epidemiológica, realizadas de forma activa, selectiva, sistemática y permanente. El objetivo de este proyecto es determinar la necesidad de implementar un sistema de vigilancia post alta, para detectar IHO en intervenciones quirúrgicas limpias, en un establecimiento hospitalario privado ubicado en retrospectiva de fichas clínicas entre septiembre a noviembre de 2007, para comparar las IHO post- alta encontradas, con las registradas por el comité de infecciones intrahospitalarias [IlH]. Los registros de cirugías a examinar son cirugías de mama, prostatectomías, tiroidectomías e histerectomías. Para la recolección de datos se utiliza una hoja de registro post alta. Los aspectos analizados la hoja de registro post alta son: tipo y distribución de cirugías, tiempo de estadía hospitalaria, registro del control postoperatorio, descripción de herida operatoria en el control postoperatorio. Se revisaron 175 fichas de las cuales se encontró una IHO adicional a la registrada por el comité de lIH. No es posible recomendar la aplicación de manera sistemática de este sistema de vigilancia, debido al bajo porcentaje de infección en Santiago. Se realiza una revisión cirugías limpias.
The third most common cause of Nosocomial Infections [NI] are Surgical Site Infections [SSI], counting for approximately 14% to 16% of all NI. Most SSls can be diagnosed while patients are still hospitalized, but some of them can only be detected once patients return to the hospital from home for their postoperative medical visit. For their identification, several epidemiologic surveillance methods are utilized, all of them carried out in an active, selective and systematic way. The purpose of this study is to determine the need of implementing a post discharge surveillance system to detect SSI in clean surgical wounds after surgery in a private facility located in Santiago. We performed a retrospective review of medical records of breast surgery, prostatectomies, thyroidectomies and hysterectomies operated between September and November 2007, looking for postdischarge SSI. We compared our findings with those reported by the NI Committee. Specially designed data collection sheet was utilized for every patient. We registered the type and distribution of surgeries, total hospital stay, postoperative medical visit and the type of surgical wound. SSls were identified, according to their clinical description. 175 patient's records were reviewed. Only one additional SSI was detected. We believe it is not possible to recommend a sistematic retrospective surveillance method like the one we described because of the low frequency of SSI in these types of surgeries.
