RESUMEN
Potentiating antitumor immunity is a promising therapeutic approach for treating a variety of cancers, including breast cancer. One potential strategy to promote antitumor immunity is targeting DNA damage response. Given that the nuclear receptor NR1D1 (also known as REV-ERBα) inhibits DNA repair in breast cancer cells, we explored the role of NR1D1 in antitumor CD8+ T-cell responses. First, deletion of Nr1d1 in MMTV-PyMT transgenic mice resulted in increased tumor growth and lung metastasis. Orthotopic allograft experiments suggested that loss of Nr1d1 in tumor cells rather than in stromal cells played a prominent role in increasing tumor progression. Comprehensive transcriptome analyses revealed that biological processes including type I IFN signaling and T cell-mediated immune responses were associated with NR1D1. Indeed, the expression of type I IFNs and infiltration of CD8+ T cells and natural killer cells in tumors were suppressed in Nr1d1-/-;MMTV-PyMT mice. Mechanistically, NR1D1 promoted DNA damage-induced accumulation of cytosolic DNA fragments and activated cGAS-STING signaling, which increased the production of type I IFNs and downstream chemokines CCL5 and CXCL10. Pharmacologic activation of NR1D1 by its ligand, SR9009, enhanced type I IFN-mediated antitumor immunity accompanied by the suppression of tumor progression and lung metastasis. Taken together, these findings reveal the critical role of NR1D1 in enhancing antitumor CD8+ T-cell responses, suggesting that NR1D1 may be a good therapeutic target for breast cancer. SIGNIFICANCE: NR1D1 suppresses breast cancer progression and lung metastasis by enhancing antitumor immunity via cGAS-STING pathway activation, which provides potential immunotherapeutic strategies for breast cancer.
Asunto(s)
Interferón Tipo I , Neoplasias Pulmonares , Animales , Ratones , Reparación del ADN , Inmunidad , Interferón Tipo I/metabolismo , Neoplasias Pulmonares/patología , Nucleotidiltransferasas/genética , Transducción de SeñalRESUMEN
Diffuse large B-cell lymphoma (DLBCL) is a prevalent and aggressive non-Hodgkin's lymphoma, and 40% of patients succumb to death. Despite numerous clinical trials aimed at developing treatment strategies beyond the conventional R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen, there have been no positive results thus far. Although the selective BCL2 inhibitor venetoclax has shown remarkable efficacy in chronic lymphocytic leukemia, its therapeutic effect in DLBCL was limited. We hypothesized that the limited therapeutic effect of venetoclax in DLBCL may be attributed to the complex expression and interactions of BCL2 family members, including BCL2. Therefore, we aimed to comprehensively analyze the expression patterns of BCL2 family members in DLBCL. We analyzed 157 patients with de novo DLBCL diagnosed at Asan Medical Center and Ajou University Hospital. The mRNA expression levels of BCL2 family members were quantified using the NanoString technology. BCL2 family members showed distinct heterogeneous expression patterns both intra- and inter-patient. Using unsupervised hierarchical cluster analysis, we were able to classify patients with similar BCL2 family expression pattern and select groups with clear prognostic features, C1 and C6. In the group with the best prognosis, C1, the expression of pro-apoptotic and pro-apoptotic BH3-only group gene expressions were increased, while anti-apoptotic group expression was significantly increased in both C1 and C6. Based on this, we generated the BCL2 signature score using the expression of pro-apoptotic genes BOK and BCL2L15, and anti-apoptotic gene BCL2. The BCL2 signature score 0 had the best prognosis, score 1/2 had intermediate prognosis, and score 3 had the worst prognosis (EFS, p = 0.0054; OS, p = 0.0011). Multivariate analysis, including COO and IPI, showed that increase in the BCL2 signature score was significantly associated with poor prognosis for EFS, independent of COO and IPI. The BCL2 signature score we proposed in this study provides information on BCL2 family deregulation based on the equilibrium of pro-versus anti-apoptotic BCL2 family, which can aid in the development of new treatment strategies for DLBCL in the future.
Asunto(s)
Linfoma de Células B Grandes Difuso , Proteínas Proto-Oncogénicas c-bcl-2 , Humanos , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Rituximab/uso terapéutico , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Ciclofosfamida/uso terapéutico , Vincristina/uso terapéutico , Prednisona/uso terapéutico , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
AIMS: In this study, we aimed to investigate previously unrecognized lipid metabolic perturbations in tamoxifen-resistant breast cancer (BC) by conducting comprehensive metabolomics and transcriptomics analysis. We identified the role of 3-hydroxy-3-methylglutary-coenzyme-A-synthase 2 (HMGCS2), a key enzyme responsible for ketogenesis, in tamoxifen-resistant BC growth. MAIN METHODS: Comprehensive metabolomics (CE-TOFMS, LC-TOFMS) and transcriptiomics analysis were performed to characterize metabolic pathways in tamoxifen-resistant BC cells. The upregulation of HMGCS2 were verified thorugh immunohistochemistry (IHC) in clinical samples obtained from patients with recurrent BC. HMGCS2 inhibitor was discovered through surface plasmon resonance analysis, enzyme assay, and additional molecular docking studies. The effect of HMGCS2 suppression on tumor growth was studied thorugh BC xenograft model, and intratumoral lipid metabolites were analyzed via MALDI-TOFMS imaging. KEY FINDINGS: We revealed that the level of HMGCS2 was highly elevated in both tamoxifen-resistant T47D sublines (T47D/TR) and clinical refractory tumor specimens from patients with ER+ breast cancer, who had been treated with adjuvant tamoxifen. Suppression of HMGCS2 in T47D/TR resulted in the accumulation of mitochondrial reactive oxygen species (mtROS) and apoptotic cell death. Further, we identified alphitolic acid, a triterpenoid natural product, as a novel HMGCS2-specific inhibitor that elevated mtROS levels and drastically retarded the growth of T47D/TR in in vitro and in vivo experiments. SIGNIFICANCE: Enhanced ketogenesis with upregulation of HMGCS2 is a potential metabolic vulnerability of tamoxifen-resistant BC that offers a new therapeutic opportunity for treating patients with ER+ BC that are refractory to tamoxifen treatment.
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Neoplasias de la Mama , Tamoxifeno , Humanos , Femenino , Tamoxifeno/farmacología , Tamoxifeno/uso terapéutico , Neoplasias de la Mama/patología , Hidroximetilglutaril-CoA Sintasa/metabolismo , Proteína HMGB2/metabolismo , Proteína HMGB2/farmacología , Simulación del Acoplamiento Molecular , Línea Celular Tumoral , Recurrencia Local de Neoplasia/tratamiento farmacológico , Apoptosis , Estrés Oxidativo , Lípidos/farmacología , Resistencia a AntineoplásicosRESUMEN
In tumor microenvironment (TME), macrophages trigger and maintain inflammatory responses that promoting tumor progression. Many cellular proteins are secreted from tumors and modulate their own TME by modulating macrophage phenotypes. Recently, we reported that interferon-γ-inducible protein 16 (IFI16), which was identified as an innate immune DNA sensor recognizing foreign DNA, triggered type â interferon responses in breast cancer (BC). However, whether IFI16 was released from BC and affects TME has not been studied. Here, we report that IFI16 and its mouse homolog Ifi202 were released from BC cells, but not from normal epithelial cells. Ifi202 induced secretion of proinflammatory cytokines such as Interleukin (IL)-1ß, IL-6, and Tumor necrosis factor-α from macrophages via binding toll-like receptor 2 and activating downstream signaling pathway. Growth of allografted mouse BC 4T1 lacking Ifi202 was suppressed and accompanied with increased infiltration and cytotoxic activity of CD8+ T lymphocytes. Further, IFI16 was detected in sera of patients with BC. High expression level of IFI16 was associated with poor prognosis in patients with BC. Taken together, our findings suggest a novel role of IFI16/Ifi202 in TME, that elicits tumor promoting inflammation and thereby shaping immunosuppressive TME in BC.
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Neoplasias de la Mama , Interferón Tipo I , Péptidos y Proteínas de Señalización Intracelular , Proteínas Nucleares , Fosfoproteínas , Animales , Ratones , Citocinas , ADN , Macrófagos/metabolismo , Fosfoproteínas/metabolismo , Microambiente Tumoral , Proteínas Nucleares/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Humanos , Neoplasias de la Mama/metabolismoRESUMEN
Although type I interferons (IFNs) play multifaceted roles during tumorigenesis and cancer treatment, the interplay between type I IFNs and estrogen signaling in breast cancer (BC) microenvironment is not well understood. Here, we report a novel function of type I IFNs in inducing aromatase expression in adipose tissues surrounding BC, which potentiates the E2-dependent growth of estrogen receptor (ER)-positive BC. First, we found that expression levels of type I IFNs correlate negatively with clinical outcome but positively with tumor grade in patients with ER-positive BC. Levels of type I IFNs were elevated in cocultured media of immune cells and BC cells, which increased aromatase expression and E2 production in Simpson-Golabi-Behmel syndrome preadipocytes. The type I IFN-induced aromatase expression was dependent on IFN-γ-inducible protein 16 (IFI16), which is encoded by an interferon-stimulated gene. At the molecular level, type I IFNs led to recruitment of HIF1α-IFI16-PRMT2 complex to the hypoxia-response element located in the aromatase PI.3/PII promoter. Next, we generated an adipocyte-specific Ifi204, which is a mouse ortholog of human IFI16, knockout mouse (Ifi204-AKO). IFNß induced E2 production in the preadipocytes isolated from the control mice, but such E2 production was far lower in the Ifi204-AKO preadipocytes. Importantly, the growth of orthotopically inoculated E0771 ER-positive mammary tumors was reduced significantly in the Ifi204-AKO mice. Taken together, our findings provide novel insights into the crosstalk between type I IFNs and estrogen signaling in the progression of ER-positive BC.
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Neoplasias de la Mama , Interferón Tipo I , Proteínas Nucleares , Fosfoproteínas , Adipocitos/metabolismo , Animales , Aromatasa/genética , Aromatasa/metabolismo , Mama/metabolismo , Neoplasias de la Mama/patología , Estrógenos/metabolismo , Femenino , Humanos , Interferón Tipo I/metabolismo , Ratones , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Microambiente TumoralRESUMEN
Tumor DNA-damage response (DDR) has an important role in driving type-I interferon (IFN)-mediated host antitumor immunity, but it is not clear how tumor DNA damage is interconnected with the immune response. Here, we report the role of IFN-γ-inducible protein 16 (IFI16) in DNA repair, which amplifies the stimulator of IFN genes (STING)-type-I IFN signaling, particularly in triple-negative breast cancer (TNBC). IFI16 is rapidly induced and accumulated to the histone-evicted DNA at double-stranded breakage (DSB) sites, where it inhibits recruitment of DDR factors. Subsequently, IFI16 increases the release of DNA fragments to the cytoplasm and induces STING-mediated type-I IFN production. Synergistic cytotoxic and immunomodulatory effects of doxorubicin and type-I IFNs are decreased upon IFI16 depletion in vivo. Furthermore, IFI16 expression correlates with improved clinical outcome in patients with TNBC treated with chemotherapy. Together, our findings suggest that type-I IFNs and IFI16 could offer potential therapeutic strategies for TNBC.
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Antineoplásicos/farmacología , ADN/metabolismo , Histonas/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo , Animales , Línea Celular Tumoral , Daño del ADN , Reparación del ADN/efectos de los fármacos , Doxorrubicina/farmacología , Sinergismo Farmacológico , Femenino , Humanos , Inmunidad , Interferón Tipo I/farmacología , Ratones Endogámicos BALB C , Proteínas Nucleares/genética , Proteínas Nucleares/farmacología , Fosfoproteínas/genética , Fosfoproteínas/farmacología , Transducción de Señal , Análisis de Matrices Tisulares , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/inmunologíaRESUMEN
BACKGROUND: Multiple myeloma (MM) is a plasma cell dyscrasia characterized by the presence of a clonal proliferation of tumor cells. Cutaneous involvement of MM is very rare and remains poorly understood. OBJECTIVE: The aim of this study was to examine the clinical and histopathologic characteristics of cutaneous involvement in MM and identify factors associated with overall survival of MM with cutaneous involvement. METHODS: The medical records of 1228 patients with MM were retrieved and analyzed. Of those patients, 14 with cutaneous involvement of MM (1.14%) were further evaluated for their clinical and histopathologic findings. RESULTS: Patients with cutaneous involvement showed significantly reduced overall survival compared with those without cutaneous involvement (median, 28 vs. 57 months; hazard ratio, 1.929; 95% confidence interval, 1.030-3.613). In subgroup analyses of patients with MM with cutaneous involvement, erythematous nodules (P = .004), multiple cutaneous lesions (P = .002), and absence of a grenz zone (P = .004) were clinicopathologic features associated with reduced overall survival after Bonferroni correction. LIMITATIONS: The retrospective design and the small sample size are the limitations. CONCLUSION: Cutaneous involvement accounted for about 1.14% of patients with MM and was associated with reduced overall survival.
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Cadenas Pesadas de Inmunoglobulina/metabolismo , Cadenas kappa de Inmunoglobulina/metabolismo , Cadenas lambda de Inmunoglobulina/metabolismo , Mieloma Múltiple/patología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/secundario , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/terapia , Prevalencia , Modelos de Riesgos Proporcionales , República de Corea , Estudios Retrospectivos , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/terapia , Tasa de SupervivenciaAsunto(s)
Neoplasias Óseas/diagnóstico , Neoplasias Óseas/cirugía , Exostosis/diagnóstico , Exostosis/cirugía , Enfermedades de la Uña/diagnóstico , Enfermedades de la Uña/cirugía , Osteocondroma/diagnóstico , Osteocondroma/cirugía , Neoplasias Óseas/complicaciones , Niño , Exostosis/complicaciones , Femenino , Humanos , Enfermedades de la Uña/complicaciones , Osteocondroma/complicacionesRESUMEN
DNA repair capacity is critical for survival of cancer cells upon therapeutic DNA damage and thus is an important determinant of susceptibility to chemotherapy in cancer patients. In this study, we identified a novel function of nuclear receptor NR1D1 in DNA repair, which enhanced chemosensitivity in breast cancer cells. NR1D1 inhibited both nonhomologous end joining and homologous recombination double-strand breaks repair, and delayed the clearance of γH2AX DNA repair foci that formed after treatment of doxorubicin. PARylation of NR1D1 by PARP1 drove its recruitment to damaged DNA lesions. Deletion of the ligand binding domain of NR1D1 that interacted with PARP1, or treatment of 6-(5H)-phenanthridinone, an inhibitor of PARP1, suppressed the recruitment of NR1D1 to DNA damaged sites, indicating PARylation as a critical step for the NR1D1 recruitment. NR1D1 inhibited recruitment of the components of DNA damage response complex such as SIRT6, pNBS1, and BRCA1 to DNA lesions. Downregulation of NR1D1 in MCF7 cells resulted in resistance to doxorubicin, both in vitro and in vivo Analysis of four public patient data sets indicated that NR1D1 expression correlates positively with clinical outcome in breast cancer patients who received chemotherapy. Our findings suggest that NR1D1 and its ligands provide therapeutic options that could enhance the outcomes of chemotherapy in breast cancer patients. Cancer Res; 77(9); 2453-63. ©2017 AACR.
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Neoplasias de la Mama/tratamiento farmacológico , Reparación del ADN/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/genética , Proteína BRCA1/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Proteínas de Ciclo Celular/genética , Roturas del ADN de Doble Cadena/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Reparación del ADN por Unión de Extremidades/efectos de los fármacos , Doxorrubicina/administración & dosificación , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células MCF-7 , Proteínas Nucleares/genética , Sirtuinas/genéticaRESUMEN
Erythroid differentiation regulator 1 (Erdr1) is known to be involved in the inflammatory process via regulating the immune system in many cutaneous disorders, such as psoriasis and rosacea. However, the role of Erdr1 in various hair loss disorders remains unclear. The aim of this study was to investigate the putative role of Erdr1 in alopecias. Skin samples from 21 patients with hair loss disorders and five control subjects were retrieved, in order to assess their expression levels of Erdr1. Results revealed that expression of Erdr1 was significantly downregulated in the epidermis and hair follicles of patients with hair loss disorders, when compared to that in the control group. In particular, the expression of Erdr1 was significantly decreased in patients with alopecia areata. We propose that Erdr1 downregulation might be involved in the pathogenesis of hair loss, and could be considered as a novel biomarker for hair loss disorders.
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Alopecia/genética , Proteínas de la Membrana/genética , Proteínas Supresoras de Tumor/genética , Alopecia/diagnóstico , Alopecia/metabolismo , Biomarcadores , Estudios de Casos y Controles , Regulación hacia Abajo , Epidermis/metabolismo , Epidermis/patología , Epitelio/metabolismo , Epitelio/patología , Expresión Génica , Folículo Piloso/metabolismo , Humanos , Inmunohistoquímica , Proteínas de la Membrana/metabolismo , Proteínas Supresoras de Tumor/metabolismoAsunto(s)
Absceso/microbiología , Infecciones por Mycobacterium no Tuberculosas/microbiología , Mycobacterium abscessus/aislamiento & purificación , Natación , Absceso/tratamiento farmacológico , Antibacterianos/uso terapéutico , Biopsia , Diagnóstico Diferencial , Femenino , Humanos , Persona de Mediana Edad , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Reacción en Cadena de la PolimerasaAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Mieloma Múltiple/tratamiento farmacológico , Síndrome de Stevens-Johnson/etiología , Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Interacciones Farmacológicas , Femenino , Humanos , Persona de Mediana Edad , Talidomida/administración & dosificación , Talidomida/efectos adversos , Vincristina/administración & dosificaciónRESUMEN
BACKGROUND: Acquired ungual fibrokeratomas are uncommon fibrous tissue tumors located in the ungual area. Though there are many reports of this entity, only some reports have reviewed the clinical features of the tumor. AIMS: The aim of this study was to clarify the clinical characteristics of acquired ungual fibrokeratomas. METHODS: We reviewed twenty patients who were treated surgically at our clinic from 2003 to 2014 for acquired ungual fibrokeratomas confirmed on histopathological examination. Our study was conducted by retrospective analysis of charts, clinical pictures and patient records. Cases of tuberous sclerosis were not included. RESULTS: Acquired ungual fibrokeratomas occurred on toenails in 16 (80%) patients and on fingernails in 4 (20%) patients. Periungual lesions were noted in 15 (75%) patients followed by intraungual lesions in 4 (20%) patients and subungual lesions in 1 (5%) patient. A longitudinal groove was observed in 80% of patients. Surgical resection was performed in all cases for both medical and cosmetic reasons. After excision, recurrence occurred in three cases. LIMITATIONS: This was a retrospective study of a limited number of patients. CONCLUSIONS: Acquired ungual fibrokeratomas occurred more commonly on toenails than on fingernails and were located in the periungual area in most patients. A longitudinal groove in the nail plate was a frequent finding. Surgical resection led to medical and cosmetic improvement with a recurrence in 3 (15%) patients.