RESUMEN
PURPOSE: The recent increase in the incidence of ductal carcinoma in situ (DCIS) has sparked debate over the classification and treatment of this disease. Although DCIS is considered a precursor lesion to invasive breast cancer, some DCIS may have more or less risk than is realized. In this study, we characterized the immune microenvironment in DCIS to determine if immune infiltrates are predictive of recurrence. METHODS: Fifty-two cases of high-grade DCIS (HG-DCIS), enriched for large lesions and a history of recurrence, were age matched with 65 cases of non-high-grade DCIS (nHG-DCIS). Immune infiltrates were characterized by single- or dual-color staining of FFPE sections for the following antigens: CD4, CD8, CD20, FoxP3, CD68, CD115, Mac387, MRC1, HLA-DR, and PCNA. Nuance multispectral imaging software was used for image acquisition. Protocols for automated image analysis were developed using CellProfiler. Immune cell populations associated with risk of recurrence were identified using classification and regression tree analysis. RESULTS: HG-DCIS had significantly higher percentages of FoxP3+ cells, CD68+ and CD68+PCNA+ macrophages, HLA-DR+ cells, CD4+ T cells, CD20+ B cells, and total tumor infiltrating lymphocytes compared to nHG-DCIS. A classification tree, generated from 16 immune cell populations and 8 clinical parameters, identified three immune cell populations associated with risk of recurrence: CD8+HLADR+ T cells, CD8+HLADR- T cells, and CD115+ cells. CONCLUSION: These findings suggest that the tumor immune microenvironment is an important factor in identifying DCIS cases with the highest risk for recurrence and that manipulating the immune microenvironment may be an efficacious strategy to alter or prevent disease progression.
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Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Carcinoma Intraductal no Infiltrante/inmunología , Carcinoma Intraductal no Infiltrante/metabolismo , Microambiente Tumoral/inmunología , Adulto , Anciano , Biomarcadores , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/terapia , Carcinoma Intraductal no Infiltrante/mortalidad , Carcinoma Intraductal no Infiltrante/terapia , Terapia Combinada , Femenino , Humanos , Recuento de Linfocitos , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Subgrupos Linfocitarios/patología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Evaluación del Resultado de la Atención al Paciente , Pronóstico , Carga TumoralRESUMEN
PURPOSE: Several pathologic staging systems characterize residual tumor in patients undergoing neoadjuvant chemotherapy for breast cancer. Pathologic complete response (pCR) is now accepted by the Food and Drug Administration as an endpoint for granting accelerated drug approval. Two other systems of post-neoadjuvant pathologic tumor staging-residual cancer burden (RCB) and the American Joint Committee on Cancer post-neoadjuvant therapy staging system (yAJCC)-have been developed to characterize residual tumors when patients do not achieve pCR. The optimal system and the ways in which these systems complement each other have not been fully determined. METHODS: Using data from the I-SPY 1 TRIAL, we compared pCR, RCB, and yAJCC as predictors of early recurrence-free survival (RFS) to identify ways to improve post-neoadjuvant pathologic evaluation. RESULTS: Among 162 patients assessed, pCR identified patients at lowest risk of recurrence, while RCB and yAJCC identified patients at highest risk. Hormone-receptor (HR) and HER2 subtypes further improved risk prediction. Recursive partitioning indicated that triple-negative or HER2+ patients with yAJCC III or RCB 3 have the highest recurrence risk, with an RFS of 27%. Our analysis also highlighted discrepancies between RCB and yAJCC stratification: 31% of patients had discrepant RCB and yAJCC scores. We identified differential treatment of lymph node involvement and tumor cellularity as drivers of these discrepancies. CONCLUSIONS: These data indicate that there is benefit to reporting both RCB and yAJCC for patients in order to identify those at highest risk of relapse.
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Neoplasias de la Mama/terapia , Mastectomía , Terapia Neoadyuvante , Estadificación de Neoplasias/métodos , Adulto , Anciano , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Mastectomía/efectos adversos , Mastectomía/mortalidad , Persona de Mediana Edad , Terapia Neoadyuvante/efectos adversos , Terapia Neoadyuvante/mortalidad , Neoplasia Residual , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
Malignant pleural mesothelioma (mesothelioma) is a highly aggressive cancer without an effective treatment. Cul4A, a scaffold protein that recruits substrates for degradation, is amplified in several human cancers, including mesothelioma. We have recently shown that Cul4A plays an oncogenic role in vitro and in a mouse model. In this study, we analysed clinical mesothelioma tumours and found moderate to strong expression of Cul4A in 70.9% (51/72) of these tumours, as shown by immunohistochemistry. In 72.2% mesothelioma tumours with increased Cul4A copy number identified by fluorescence in situ hybridization analysis, Cul4A protein expression was moderate to strong. Similarly, Cul4A was overexpressed and Cul4A copy number was increased in human mesothelioma cell lines. Because Gli1 is highly expressed in human mesothelioma cells, we compared Cul4A and Gli1 expression in mesothelioma tumours and found their expression associated (P < 0.05, chi-square). In mesothelioma cell lines, inhibiting Cul4A by siRNA decreased Gli1 expression, suggesting that Gli1 expression is, at least in part, regulated by Cul4A in mesothelioma cells. Our results suggest a linkage between Cul4A and Gli1 expression in human mesothelioma.
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Proteínas Cullin/metabolismo , Neoplasias Pulmonares/metabolismo , Mesotelioma/metabolismo , Factores de Transcripción/metabolismo , Estudios de Casos y Controles , Línea Celular Tumoral , Distribución de Chi-Cuadrado , Proteínas Cullin/genética , Dosificación de Gen , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mesotelioma/genética , Mesotelioma/patología , Mesotelioma Maligno , Neoplasias Pleurales/metabolismo , Neoplasias Pleurales/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Factores de Transcripción/genética , Proteína con Dedos de Zinc GLI1RESUMEN
INTRODUCTION: The molecular biology involving neoadjuvant chemotherapy (NAC) response is poorly understood. To elucidate the impact of NAC on the breast cancer transcriptome and its association with clinical outcome, we analyzed gene expression data derived from serial tumor samples of patients with breast cancer who received NAC in the I-SPY 1 TRIAL. METHODS: Expression data were collected before treatment (T1), 24-96 hours after initiation of chemotherapy (T2) and at surgery (TS). Expression levels between T1 and T2 (T1 vs. T2; n = 36) and between T1 and TS (T1 vs. TS; n = 39) were compared. Subtype was assigned using the PAM50 gene signature. Differences in early gene expression changes (T2 - T1) between responders and nonresponders, as defined by residual cancer burden, were evaluated. Cox proportional hazards modeling was used to identify genes in residual tumors associated with recurrence-free survival (RFS). Pathway analysis was performed with Ingenuity software. RESULTS: When we compared expression profiles at T1 vs. T2 and at T1 vs. TS, we detected significantly altered expression of 150 and 59 transcripts, respectively. We observed notable downregulation of proliferation and immune-related genes at T2. Lower concordance in subtype assignment was observed between T1 and TS (62 %) than between T1 and T2 (75 %). Analysis of early gene expression changes (T2 - T1) revealed that decreased expression of cell cycle inhibitors was associated with poor response. Increased interferon signaling (TS - T1) and high expression of cell proliferation genes in residual tumors (TS) were associated with reduced RFS. CONCLUSIONS: Serial gene expression analysis revealed candidate immune and proliferation pathways associated with response and recurrence. Larger studies incorporating the approach described here are warranted to identify predictive and prognostic biomarkers in the NAC setting for specific targeted therapies. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00033397 . Registered 9 Apr 2002.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Perfilación de la Expresión Génica , Transcriptoma , Adulto , Anciano , Biomarcadores de Tumor , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Ciclo Celular/genética , Análisis por Conglomerados , Femenino , Humanos , Antígeno Ki-67/metabolismo , Persona de Mediana Edad , Terapia Neoadyuvante , Clasificación del Tumor , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Pronóstico , Transducción de Señal , Factores de Tiempo , Resultado del Tratamiento , Carga TumoralRESUMEN
Cullin4A (Cul4A) is a scaffold protein that assembles cullin-RING ubiquitin ligase (E3) complexes and regulates many cellular events, including cell survival, development, growth and cell cycle control. Our previous study suggested that Cul4A is oncogenic in vitro, but its oncogenic role in vivo has not been studied. Here, we used a Cul4A transgenic mouse model to study the potential oncogenic role of Cul4A in lung tumour development. After Cul4A over-expression was induced in the lungs for 32 weeks, atypical epithelial cells were observed. After 40 weeks, lung tumours were visible and were characterized as grade I or II adenocarcinomas. Immunohistochemistry (IHC) revealed decreased levels of Cul4A-associated proteins p21(CIP1) and tumour suppressor p19(ARF) in the lung tumours, suggesting that Cul4A regulated their expression in these tumours. Increased levels of p27(KIP1) and p16(INK4a) were also detected in these tumours. Moreover, the protein level of DNA replication licensing factor CDT1 was decreased. Genomic instability in the lung tumours was further analysed by the results from pericentrin protein expression and array comparative genomic hybridization analysis. Furthermore, knocking down Cul4A expression in lung cancer H2170 cells increased their sensitivity to the chemotherapy drug cisplatin in vitro, suggesting that Cul4A over-expression is associated with cisplatin resistance in the cancer cells. Our findings indicate that Cul4A is oncogenic in vivo, and this Cul4A mouse model is a tool in understanding the mechanisms of Cul4A in human cancers and for testing experimental therapies targeting Cul4A.
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Adenocarcinoma/metabolismo , Transformación Celular Neoplásica/metabolismo , Proteínas Cullin/metabolismo , Neoplasias Pulmonares/metabolismo , Pulmón/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma del Pulmón , Animales , Antineoplásicos/farmacología , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Cisplatino/farmacología , Proteínas Cullin/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Inhibidor p19 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Inestabilidad Genómica , Humanos , Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , Ratones Transgénicos , Clasificación del Tumor , Antígeno Nuclear de Célula en Proliferación/metabolismo , Interferencia de ARN , Factores de Tiempo , Transfección , Regulación hacia ArribaRESUMEN
Retrospective clinical studies have used immune-based biomarkers, alone or in combination, to predict survival outcomes for women with breast cancer (BC); however, the limitations inherent to immunohistochemical analyses prevent comprehensive descriptions of leukocytic infiltrates, as well as evaluation of the functional state of leukocytes in BC stroma. To more fully evaluate this complexity, and to gain insight into immune responses after chemotherapy (CTX), we prospectively evaluated tumor and nonadjacent normal breast tissue from women with BC, who either had or had not received neoadjuvant CTX before surgery. Tissues were evaluated by polychromatic flow cytometry in combination with confocal immunofluorescence and immunohistochemical analysis of tissue sections. These studies revealed that activated T lymphocytes predominate in tumor tissue, whereas myeloid lineage cells are more prominant in "normal" breast tissue. Notably, residual tumors from an unselected group of BC patients treated with neoadjuvant CTX contained increased percentages of infiltrating myeloid cells, accompanied by an increased CD8/CD4 T-cell ratio and higher numbers of granzyme B-expressing cells, compared with tumors removed from patients treated primarily by surgery alone. These data provide an initial evaluation of differences in the immune microenvironment of BC compared with nonadjacent normal tissue and reveal the degree to which CTX may alter the complexity and presence of selective subsets of immune cells in tumors previously treated in the neoadjuvant setting.
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Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Leucocitos/inmunología , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Linaje de la Célula/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Citotoxicidad Inmunológica/efectos de los fármacos , Femenino , Humanos , Leucocitos/efectos de los fármacos , Leucocitos/patología , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Células Mieloides/efectos de los fármacos , Células Mieloides/inmunología , Células Mieloides/patología , Terapia Neoadyuvante , Neoplasia Residual/inmunología , Neoplasia Residual/patología , Fenotipo , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/patologíaRESUMEN
Protein kinase CK2 is frequently elevated in a variety of human cancers. The Notch1 signalling pathway has been implicated in stem cell maintenance and its aberrant activation has been shown in several types of cancer including lung cancer. Here, we show, for the first time, that CK2α is a positive regulator of Notch1 signalling in lung cancer cell lines A549 and H1299. We found that Notch1 protein level was reduced after CK2α silencing. Down-regulation of Notch1 transcriptional activity was demonstrated after the silencing of CK2α in lung cancer cells. Furthermore, small-molecule CK2α inhibitor CX-4945 led to a dose-dependent inhibition of Notch1 transcriptional activity. Conversely, forced overexpression of CK2α resulted in an increase in Notch1 transcriptional activity. Finally, the inhibition of CK2α led to a reduced proportion of stem-like CD44 + /CD24- cell population. Thus, we report that the inhibition of CK2α down-regulates Notch1 signalling and subsequently reduces a cancer stem-like cell population in human lung cancer cells. Our data suggest that CK2α inhibitors may be beneficial to the lung cancer patients with activated Notch1 signalling.
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Quinasa de la Caseína II/antagonistas & inhibidores , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/metabolismo , Receptor Notch1/metabolismo , Transducción de Señal , Antígeno CD24/metabolismo , Quinasa de la Caseína II/metabolismo , Línea Celular Tumoral , ADN/metabolismo , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo , Citometría de Flujo , Humanos , Receptores de Hialuranos/metabolismo , Inmunohistoquímica , Naftiridinas/farmacología , Células Madre Neoplásicas/citología , Fenazinas , Fenotipo , ARN Interferente Pequeño/metabolismo , Transcripción GenéticaRESUMEN
Diving-related activities may constitute a major threat to coral reefs. This study aimed to quantify the impact of diving in Hong Kong on hard corals and understand how socio-economic characteristics and experience level of divers influence diver-inflicted damage. We recorded and analysed the underwater behaviour of 81 recreational divers. On average, a diver was in contact with marine biota 14.7 times with about 40% of contacts involved corals and 38% were damaging contacts with corals or other biota in a single dive. The most harm-inflicting groups included inexperienced and camera-carrying divers. Although Hong Kong divers did not make many damaging contacts with corals, there is still an imminent need to determine the scale of damage from diving activities on the marine ecosystem given the rapid development of marine-based tourism and the limited coral-inhabited areas in Hong Kong where the marine environment is already under stress from anthropogenic activities.
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Buceo , Animales , Antozoos , Conservación de los Recursos Naturales , Ecosistema , Hong Kong , HumanosRESUMEN
Neoadjuvant chemotherapy for breast cancer allows individual tumor response to be assessed depending on molecular subtype, and to judge the impact of response to therapy on recurrence-free survival (RFS). The multicenter I-SPY 1 TRIAL evaluated patients with ≥ 3 cm tumors by using early imaging and molecular signatures, with outcomes of pathologic complete response (pCR) and RFS. The current analysis was performed using data from patients who had molecular profiles and did not receive trastuzumab. The various molecular classifiers tested were highly correlated. Categorization of breast cancer by molecular signatures enhanced the ability of pCR to predict improvement in RFS compared to the population as a whole. In multivariate analysis, the molecular signatures that added to the ability of HR and HER2 receptors, clinical stage, and pCR in predicting RFS included 70-gene signature, wound healing signature, p53 mutation signature, and PAM50 risk of recurrence. The low risk signatures were associated with significantly better prognosis, and also identified additional patients with a good prognosis within the no pCR group, primarily in the hormone receptor positive, HER-2 negative subgroup. The I-SPY 1 population is enriched for tumors with a poor prognosis but is still heterogeneous in terms of rates of pCR and RFS. The ability of pCR to predict RFS is better by subset than it is for the whole group. Molecular markers improve prediction of RFS by identifying additional patients with excellent prognosis within the no pCR group.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Terapia Neoadyuvante , Recurrencia Local de Neoplasia , Adulto , Anciano , Antraciclinas/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Biomarcadores de Tumor/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Ensayos Clínicos como Asunto , Supervivencia sin Enfermedad , Femenino , Perfilación de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Análisis Multivariante , Neoplasia Residual , Modelos de Riesgos Proporcionales , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Taxoides/administración & dosificación , TrastuzumabRESUMEN
PURPOSE: Macrophages play a major role in inflammatory processes and have been associated with poor prognosis in a variety of cancers, including breast cancer. Previously, we investigated the relationship of a subset of tumor-associated macrophages (PCNA(+) TAMs) with clinicopathologic characteristics of breast cancer. We reported that high PCNA(+) TAM counts were associated with hormone receptor (HR)-negative, high-grade tumors and early recurrence. To further understand the significance of elevated PCNA(+) TAMs and the functionality of TAMs, we examined the expression of S100A8/S100A9 with the antibody Mac387. The heterodimeric S100A8/S100A9 complex plays a role in inflammation and is increased in several cancer types. METHODS: We performed immunohistochemistry using the Mac387 antibody on 367 invasive human breast cancer cases. Results were compared to previous PCNA(+) TAM counts and were correlated with patient outcomes adjusting for HR status and histologic grade. RESULTS: Like PCNA(+) TAMs, high Mac387 counts were associated with HR negativity, high tumor grade, younger age, and decreased recurrence-free survival. Mac387, however, appears to identify both a subset of macrophages and a subset of tumor cells. The concordance between Mac387 and PCNA(+) TAM counts was low and cases that had both high Mac387 and high PCNA(+) TAMs counts had a stronger association with early recurrence. CONCLUSIONS: The presence of high numbers of PCNA(+) TAMs and Mac387-positive cells in breast cancers with poor outcomes may implicate a subset of TAMs in breast cancer pathogenesis, and may ultimately serve to develop potential cellular targets for therapeutic interventions.
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Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/mortalidad , Macrófagos/patología , Recurrencia Local de Neoplasia/mortalidad , Antígeno Nuclear de Célula en Proliferación/metabolismo , Adulto , Anticuerpos Monoclonales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Calgranulina A/metabolismo , Calgranulina B/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Técnicas para Inmunoenzimas , Macrófagos/metabolismo , Persona de Mediana Edad , Clasificación del Tumor , Invasividad Neoplásica , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia , Análisis de Matrices TisularesRESUMEN
The chemokine CXCL12 and its receptors, CXCR4 and CXCR7, are involved in tumour progression, metastasis, and survival. We investigated the expression of CXCR4, CXCL12, and CXCR7 in malignant pleural mesothelioma to determine if they are possible biomarkers and potential therapeutic targets. Forty-one mesothelioma tumour tissues, ten normal human pleural tissues, and two mesothelioma cell lines were stained with anti-CXCR4, anti-CXCL12, anti-CXCR7, and anti-p-Akt antibodies. RT-PCR was performed to determine the expression of CXCR4, CXCL12, and CXCR7 in six human mesothelioma cell lines (H28, 211H, H2052, ms-1, H290, and H513) and one human normal mesothelial cell line, LP9. These seven cell lines were also stained with anti-CXCR7. We found that CXCR4 and CXCL12 were expressed in 97.6% and 78.0% mesothelioma tissue samples, concurrently with strong expression of p-Akt (R(2) = 0.739 and 0.620, respectively). In addition, CXCR7 expression was weaker than CXCR4 expression in mesothelioma tissues. Furthermore, RT-PCR showed that CXCR4 and CXCL12 were overexpressed in 5/6 mesothelioma cell lines (211H, H2052, ms-1, H290, and H513), whereas CXCR7 was overexpressed in only 2/6 (H513 and H2052). Moreover, we found that the CXCR4 antagonist AMD3100 inhibited the growth of all five mesothelioma cell lines that overexpress CXCR4 and CXCL12. Our results suggest that the Akt-mTOR pathway is involved during the interruption of the CXCL12/CXCR4 axis in these five mesothelioma cell lines. In conclusion, CXCR4 and CXCL12 are highly expressed in most mesothelioma cell lines and tumour tissues, suggesting that CXCR4 and CXCL12 may be used as biomarkers for patients with mesothelioma. The CXCL12-CXCR4 interaction may be a potential therapeutic target for mesothelioma.
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Quimiocina CXCL12/metabolismo , Mesotelioma/metabolismo , Neoplasias Pleurales/metabolismo , Receptores CXCR4/metabolismo , Receptores CXCR/metabolismo , Bencilaminas , Biomarcadores de Tumor/metabolismo , Proliferación Celular , Supervivencia Celular , Ciclamas , Compuestos Heterocíclicos , Humanos , Mesotelioma/patología , Proteínas de Neoplasias/metabolismo , Proteína Oncogénica v-akt/metabolismo , Neoplasias Pleurales/patología , Receptores CXCR4/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Células Tumorales CultivadasRESUMEN
African American and Hispanic women develop more triple negative breast cancer at younger ages than Caucasian women. The frequently observed association between race and socioeconomic status (SES) has confounded our understanding of the outcomes disparities seen in these groups. Given the association between inflammatory cells and high-grade, triple negative tumors, we sought to investigate whether differences in the presence of these cells varies by race. We evaluated breast tumor specimens for the presence PCNA+ tumor-associated macrophages (TAMs) in consecutive cases from a county hospital serving primarily un- or under-insured patients. All patients in this cohort had elevated PCNA + TAM levels. Higher PCNA + TAM counts were associated with hormone receptor (HR) negative tumors and non-Caucasian ethnicity. Hispanic women specifically had significantly higher PCNA + TAM counts than Caucasian patients and shorter disease-free survival. These findings implicate immune function in the development of aggressive breast cancer and suggest a possible link between SES and the inflammatory response.
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Negro o Afroamericano , Neoplasias de la Mama/etnología , Carcinoma Ductal de Mama/etnología , Hispánicos o Latinos , Macrófagos/metabolismo , Recurrencia Local de Neoplasia , Antígeno Nuclear de Célula en Proliferación/metabolismo , Adulto , Anciano , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/mortalidad , Carcinoma Ductal de Mama/patología , Recuento de Células , Supervivencia sin Enfermedad , Femenino , Disparidades en Atención de Salud , Humanos , Estimación de Kaplan-Meier , Macrófagos/patología , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estados Unidos , Población BlancaRESUMEN
The purpose of this study is to determine the biologic impact of short-term lipophilic statin exposure on in situ and invasive breast cancer through paired tissue, blood and imaging-based biomarkers. A perioperative window trial of fluvastatin was conducted in women with a diagnosis of DCIS or stage 1 breast cancer. Patients were randomized to high dose (80 mg/day) or low dose (20 mg/day) fluvastatin for 3-6 weeks before surgery. Tissue (diagnostic core biopsy/final surgical specimen), blood, and magnetic resonance images were obtained before/after treatment. The primary endpoint was Ki-67 (proliferation) reduction. Secondary endpoints were change in cleaved caspase-3 (CC3, apoptosis), MRI tumor volume, and serum C-reactive protein (CRP, inflammation). Planned subgroup analyses compared disease grade, statin dose, and estrogen receptor status. Forty of 45 patients who enrolled completed the protocol; 29 had paired Ki-67 primary endpoint data. Proliferation of high grade tumors decreased by a median of 7.2% (P = 0.008), which was statistically greater than the 0.3% decrease for low grade tumors. Paired data for CC3 showed tumor apoptosis increased in 38%, remained stable in 41%, and decreased in 21% of subjects. More high grade tumors had an increase in apoptosis (60 vs. 13%; P = 0.015). Serum CRP did not change, but cholesterol levels were significantly lower post statin exposure (P < 0.001). Fluvastatin showed measurable biologic changes by reducing tumor proliferation and increasing apoptotic activity in high-grade, stage 0/1 breast cancer. Effects were only evident in high grade tumors. These results support further evaluation of statins as chemoprevention for ER-negative high grade breast cancers.
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Apoptosis , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma Intraductal no Infiltrante/tratamiento farmacológico , Ácidos Grasos Monoinsaturados/uso terapéutico , Regulación Neoplásica de la Expresión Génica , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Indoles/uso terapéutico , Adulto , Anciano , Proteína C-Reactiva/biosíntesis , Caspasa 3/biosíntesis , Proliferación Celular/efectos de los fármacos , Femenino , Fluvastatina , Humanos , Antígeno Ki-67/biosíntesis , Persona de Mediana EdadRESUMEN
INTRODUCTION: One in ten women over the age of 65 will develop breast cancer. Despite this high incidence of breast cancer among older women, social support for them is often inadequate. This paper describes a qualitative study of the impact of a breast cancer diagnosis on older women from racially/ethnically diverse populations and their subsequent need for social support. METHODS: Forty-seven older African American, Asian American, Caucasian and Latina women between the ages of 65 to 83 participated in a larger study examining the impact of breast cancer on women from racially/ethnically diverse populations and the meaning and nature of social support. The women completed an in-depth qualitative interview on the psychosocial impact of breast cancer and the meaning and nature of social support. RESULTS AND CONCLUSION: The results indicate that there are variations in reactions to a breast cancer diagnosis among older women, and that these reactions impact their experiences with seeking social support at diagnosis and during treatment. Respondents were concerned about their aging bodies, potential dependency on others, and loss of autonomy. At the same time, the severity of cancer treatment and existing co-morbidities often meant they needed to learn to receive support, and to reach out if they had no support. The implications of these findings underscore the older cancer patient's need to strengthen her supportive networks at the time of diagnosis, during treatment, and post-treatment.
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Neoplasias de la Mama/psicología , Apoyo Social , Factores de Edad , Anciano , Anciano de 80 o más Años , Comorbilidad , Femenino , Humanos , Investigación Cualitativa , San FranciscoRESUMEN
INTRODUCTION: Breast cancer remains one of the leading causes of morbidity and mortality for all women in the US. Current research has focused on the psychological relationship and not the sociological relationship between emotions and the experience of breast cancer survivors. This paper focuses on the emotion work involved in self-disclosing a breast cancer diagnosis in a racially or ethnically diverse population. METHODS: The participants (n = 176) selected for this study were African American, Asian American, Latina, and Caucasian women who had been diagnosed with stages 0, I, or II breast cancer within the past 4 years. They completed an in-depth qualitative interview on self-disclosure and social support. FINDINGS: The results indicate self-disclosing was done at a time when important decisions about treatment needed to be made. Different strategies for disclosure were used, all of which entailed emotion work. Respondents talked about the various elements of emotion work in the disclosure process including: managing others' worry, protecting and soothing others, and educating and instructing others. For many respondents, disclosure without calculating emotional management meant opening up to others which meant support and an increase in emotional resources. CONCLUSIONS: The findings in this paper have implications for women with breast cancer and demonstrate the need for women to be involved in honest disclosure and less emotional management of others' feelings. There is also a need for education about the nature of the cancer experience among people who are not well educated about the treatment and consequences of cancer. This need may be even stronger among racial and ethnic minorities.
Asunto(s)
Neoplasias de la Mama/psicología , Conocimientos, Actitudes y Práctica en Salud , Autorrevelación , Revelación de la Verdad , Adaptación Psicológica , Adulto , Negro o Afroamericano/estadística & datos numéricos , Anciano , Actitud Frente a la Salud/etnología , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/patología , California/epidemiología , Niño , Emociones , Relaciones Familiares , Miedo/psicología , Femenino , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Relaciones Interpersonales , Estudios Longitudinales , Persona de Mediana Edad , Relaciones Madre-Hijo , Estadificación de Neoplasias , Calidad de Vida , Apoyo Social , Sobrevivientes/psicología , Población Blanca/estadística & datos numéricosRESUMEN
Myoepithelial cells play key roles in normal mammary gland development and in limiting pre-invasive to invasive breast tumor progression, yet their differentiation and perturbation in ductal carcinoma in situ (DCIS) are poorly understood. Here, we investigated myoepithelial cells in normal breast tissues of BRCA1 and BRCA2 germline mutation carriers and in non-carrier controls, and in sporadic DCIS. We found that in the normal breast of non-carriers, myoepithelial cells frequently co-express the p63 and TCF7 transcription factors and that p63 and TCF7 show overlapping chromatin peaks associated with differentiated myoepithelium-specific genes. In contrast, in normal breast tissues of BRCA1 mutation carriers the frequency of p63+TCF7+ myoepithelial cells is significantly decreased and p63 and TCF7 chromatin peaks do not overlap. These myoepithelial perturbations in normal breast tissues of BRCA1 germline mutation carriers may play a role in their higher risk of breast cancer. The fraction of p63+TCF7+ myoepithelial cells is also significantly decreased in DCIS, which may be associated with invasive progression.
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Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Carcinoma Ductal de Mama/metabolismo , Mutación/genética , Animales , Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Ductal de Mama/genética , Línea Celular Tumoral , Proliferación Celular/genética , Proliferación Celular/fisiología , Femenino , Técnica del Anticuerpo Fluorescente , Mutación de Línea Germinal/genética , Humanos , Inmunohistoquímica , Ratones , Factor 1 de Transcripción de Linfocitos T/genética , Factor 1 de Transcripción de Linfocitos T/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Malignant pleural mesothelioma (MPM) is an aggressive cancer for which more effective treatments are needed. In this study, strong to moderate staining of MET and ERK5 was detected in 67.1 and 48% of the analyzed 73 human mesothelioma tumors, and significant correlation of MET and ERK5 expression was identified (P<0.05). We evaluated the doublecortin-like kinase 1 (DCLK1) expression in human mesothelioma tumors. Our results showed that 50.7% of the immunohistochemistry analyzed human mesothelioma tumors have strong to moderate staining of DCLK1, and its expression is significantly correlated with MET or ERK5 expression (P<0.05). Also, the upregulation of DCLK1 is correlated with poor prognosis in MPM patients (P=0.0235). To investigate whether DCLK1 is downstream of MET/ERK5 signaling in human mesothelioma, the effect of DCLK1 expression was analyzed after treatments with either the MET inhibitor XL184 or the ERK5 inhibitor XMD8-92 in human mesothelioma cell lines. Our results showed that the MET inhibitor XL184 reduced the expression of phosphoERK5 and DCLK1 expression in human mesothelioma cell lines. In addition, the ERK5 inhibitor XMD8-92 reduced the expression of phospho-ERK5 and DCLK1 expression in human mesothelioma cell lines. Furthermore, XML184 and XMD8-92 treatment impaired invasion and tumor sphere formation ability of H290 mesothelioma cells. These results suggest that DCLK1 is regulated by MET/ERK5 signaling in human mesothelioma, and the MET/ERK5/DCLK1 signaling cascade could be further developed into a promising therapeutic target against mesothelioma.
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Biomarcadores de Tumor/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias Pulmonares/patología , Mesotelioma/patología , Proteína Quinasa 7 Activada por Mitógenos/metabolismo , Neoplasias Pleurales/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismo , Anciano , Apoptosis , Movimiento Celular , Proliferación Celular , Quinasas Similares a Doblecortina , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Mesotelioma/metabolismo , Mesotelioma Maligno , Neoplasias Pleurales/metabolismo , Pronóstico , Tasa de Supervivencia , Células Tumorales CultivadasRESUMEN
BACKGROUND: Imaging patterns of benign proliferative processes often complicate the assessment of ductal carcinoma in situ (DCIS) by magnetic resonance imaging (MRI). We investigated the pathologic and biologic characteristics of false positive enhancement by breast MRI. METHODS: DCIS (n = 45), benign (n = 5), and false-positive (MRI enhancement and nonmalignant pathology) (n = 10) cases were characterized by immunohistochemistry and MRI features. RESULTS: For DCIS cases, images that overestimated pathologic size had heterogeneous enhancement on MR, were estrogen receptor positive, and were low grade by pathology. False-positives had higher rates of proliferation, angiogenesis, and inflammation compared with benign tissue but lower values than DCIS. Benign proliferative processes accounted for all false-positive and size overestimated cases. CONCLUSIONS: Lesions that enhance on MRI have higher proliferation, angiogenesis, and inflammation compared with nonproliferative breast tissue. Benign proliferative processes often enhance on MRI and are difficult to differentiate from low-grade, ER+ DCIS lesions. False-positive MRI enhancement may reflect a spectrum of change within high-risk tissue.
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Enfermedades de la Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carcinoma Intraductal no Infiltrante/metabolismo , Carcinoma Intraductal no Infiltrante/patología , Imagen por Resonancia Magnética , Antígenos CD/metabolismo , Antígenos CD34/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Enfermedades de la Mama/metabolismo , Estudios de Casos y Controles , Reacciones Falso Positivas , Femenino , Humanos , Antígeno Ki-67/metabolismo , Persona de Mediana Edad , Carga TumoralRESUMEN
BACKGROUND: Maintenance of genomic integrity is essential to ensure normal organismal development and to prevent diseases such as cancer. PR-Set7 (also known as Set8) is a cell cycle regulated enzyme that catalyses monomethylation of histone 4 at Lys20 (H4K20me1) to promote chromosome condensation and prevent DNA damage. Recent studies show that CRL4CDT2-mediated ubiquitylation of PR-Set7 leads to its degradation during S phase and after DNA damage. This might occur to ensure appropriate changes in chromosome structure during the cell cycle or to preserve genome integrity after DNA damage. METHODS: We developed a new model of lung tumor development in mice harboring a conditionally expressed allele of Cul4A. We have therefore used a mouse model to demonstrate for the first time that Cul4A is oncogenic in vivo. With this model, staining of PR-Set7 in the preneoplastic and tumor lesions in AdenoCre-induced mouse lungs was performed. Meanwhile we identified higher protein level changes of γ-tubulin and pericentrin by IHC. RESULTS: The level of PR-Set7 down-regulated in the preneoplastic and adenocarcinomous lesions following over-expression of Cul4A. We also identified higher levels of the proteins pericentrin and γ-tubulin in Cul4A mouse lungs induced by AdenoCre. CONCLUSIONS: PR-Set7 is a direct target of Cul4A for degradation and involved in the formation of lung tumors in the conditional Cul4A transgenic mouse model.
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Proteínas Cullin/metabolismo , N-Metiltransferasa de Histona-Lisina/metabolismo , Neoplasias Pulmonares/metabolismo , Animales , Ciclo Celular , Proteínas Cullin/genética , Modelos Animales de Enfermedad , Regulación hacia Abajo , N-Metiltransferasa de Histona-Lisina/genética , Histonas/metabolismo , Humanos , Pulmón/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/fisiopatología , Ratones , Ratones Transgénicos , Proteolisis , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismoRESUMEN
BACKGROUND: Lung cancer is the leading cause of morbidity and death worldwide. Although the available lung cancer animal models have been informative and further propel our understanding of human lung cancer, they still do not fully recapitulate the complexities of human lung cancer. The pathogenesis of lung cancer remains highly elusive because of its aggressive biologic nature and considerable heterogeneity, compared to other cancers. The association of Cul4A amplification with aggressive tumor growth and poor prognosis has been suggested. Our previous study suggested that Cul4A is oncogenic in vitro, but its oncogenic role in vivo has not been studied. METHODS: Viral delivery approaches have been used extensively to model cancer in mouse models. In our experiments, we used Cre-recombinase induced overexpression of the Cul4A gene in transgenic mice to study the role of Cul4A on lung tumor initiation and progression and have developed a new model of lung tumor development in mice harboring a conditionally expressed allele of Cul4A. RESULTS: Here we show that the use of a recombinant adenovirus expressing Cre-recombinase ("AdenoCre") to induce Cul4A overexpression in the lungs of mice allows controls of the timing and multiplicity of tumor initiation. Following our mouse models, we are able to study the potential role of Cul4A in the development and progression in pulmonary adenocarcinoma as well. CONCLUSION: Our findings indicate that Cul4A is oncogenic in vivo, and this mouse model is a tool in understanding the mechanisms of Cul4A in human cancers and for testing experimental therapies targeting Cul4A.