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1.
Neuro Oncol ; 26(Supplement_3): iii1-iii53, 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38709657

RESUMO

Recent analyses have shown that, whereas cancer survival overall has been improving, it has not improved for adolescents and young adults ages 15-39 years (AYA). The clinical care of AYA with primary brain and other central nervous system (CNS) tumors (BT) is complicated by the fact that the histopathologies of such tumors in AYA differ from their histopathologies in either children (ages 0-14 years) or older adults (ages 40+ years). The present report, as an update to a 2016 publication from the Central Brain Tumor Registry of the United States and the American Brain Tumor Association, provides in-depth analyses of the epidemiology of primary BT in AYA in the United States and is the first to provide biomolecular marker-specific statistics and prevalence by histopathology for both primary malignant and non-malignant BT in AYA. Between 2016 and 2020, the annual average age-specific incidence rate (AASIR) of primary malignant and non-malignant BT in AYA was 12.00 per 100,000 population, an average of 12,848 newly diagnosed cases per year. During the same period, an average of 1,018 AYA deaths per year were caused by primary malignant BT, representing an annual average age-specific mortality rate of 0.96 per 100,000 population. When primary BT were categorized by histopathology, pituitary tumors were the most common (36.6%), with an AASIR of 4.34 per 100,000 population. Total incidence increased with age overall; when stratified by sex, the incidence was higher in females than males at all ages. Incidence rates for all primary BT combined and for non-malignant tumors only were highest for non-Hispanic American Indian/Alaska Native individuals, whereas malignant tumors were more frequent in non-Hispanic White individuals, compared with other racial/ethnic groups. On the basis of histopathology, the most common molecularly defined tumor was diffuse glioma (an AASIR of 1.51 per 100,000). Primary malignant BT are the second most common cause of cancer death in the AYA population. Incidence rates of primary BT overall, as well as specific histopathologies, vary significantly by age. Accordingly, an accurate statistical assessment of primary BT in the AYA population is vital for better understanding the impact of these tumors on the US population and to serve as a reference for afflicted individuals, for researchers investigating new therapies, and for clinicians treating these patients.


Assuntos
Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Sistema de Registros , Humanos , Adolescente , Adulto Jovem , Estados Unidos/epidemiologia , Masculino , Feminino , Adulto , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/patologia , Neoplasias do Sistema Nervoso Central/epidemiologia , Neoplasias do Sistema Nervoso Central/patologia , Sistema de Registros/estatística & dados numéricos , Incidência , Pré-Escolar , Criança , Recém-Nascido , Lactente
2.
Neuro Oncol ; 26(4): 596-608, 2024 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-38071654

RESUMO

Despite major strides in cancer research and therapy, these advances have not been equitable across race and ethnicity. Historically marginalized groups (HMG) are more likely to have inadequate preventive screening, increased delays in diagnosis, and poor representation in clinical trials. Notably, Black, Hispanic, and Indigenous people represent 30% of the population but only 9% of oncology clinical trial participants. As a result, HMGs lack equitable access to novel therapies, contradicting the principle of distributive justice, as enshrined in the Belmont report, which demands the equitable selection of subjects in research involving human subjects. The lack of clinical trial diversity also leads to low generalizability and potentially harmful medical practices. Specifically, patients with brain cancer face unique barriers to clinical trial enrollment and completion due to disease-specific neurologic and treatment-induced conditions. Collectively, the intersection of these disease-specific conditions with social determinants of health fosters a lack of diversity in clinical trials. To ameliorate this disparity in neuro-oncology clinical trial participation, we present interventions focused on improving engagement of HMGs. Proposals range from inclusive trial design, decreasing barriers to care, expanding trial eligibility, access to tumor profiling for personalized medical trials, setting reasonable metrics and goals for accrual, working with patient community stakeholders, diversifying the neuro-oncology workforce, and development of tools to overcome biases with options to incentivize equity. The diversification of participation amongst neuro-oncology clinical trials is imperative. Equitable access and inclusion of HMG patients with brain tumors will not only enhance research discoveries but will also improve patient care.


Assuntos
Neoplasias Encefálicas , Humanos , Neoplasias Encefálicas/terapia , Oncologia , Etnicidade
3.
Lancet Oncol ; 24(8): e344-e354, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37541280

RESUMO

Brain metastases are an increasing global public health concern, even as survival rates improve for patients with metastatic disease. Both metastases and the sequelae of their treatment are key determinants of the inter-related priorities of patient survival, function, and quality of life, mandating a multidimensional approach to clinical care and research. At a virtual National Cancer Institute Workshop in September, 2022, key stakeholders convened to define research priorities to address the crucial areas of unmet need for patients with brain metastases to achieve meaningful advances in patient outcomes. This Policy Review outlines existing knowledge gaps, collaborative opportunities, and specific recommendations regarding consensus priorities and future directions in brain metastases research. Achieving major advances in research will require enhanced coordination between the ongoing efforts of individual organisations and consortia. Importantly, the continual and active engagement of patients and patient advocates will be necessary to ensure that the directionality of all efforts reflects what is most meaningful in the context of patient care.


Assuntos
Pesquisa Biomédica , Neoplasias Encefálicas , Estados Unidos , Humanos , Qualidade de Vida , National Cancer Institute (U.S.) , Consenso , Neoplasias Encefálicas/terapia
4.
Future Oncol ; 19(2): 173-188, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36974606

RESUMO

Aim: To develop a cognitive dysfunction (CD) focused questionnaire to evaluate caregiver burden in glioblastoma. Materials & methods: The survey was developed from stakeholder consultations and a pilot study, and disseminated at eight US academic cancer centers. Caregivers self-reported caring for an adult with glioblastoma and CD. Results: The 89-item survey covered demographics, CD symptoms and caregiver burden domains. Among 185 caregivers, most were white, educated females and reported memory problems as the most common CD symptom. An exposure-effect was observed, with increase in number of CD symptoms significantly associated with greater caregiver burden. Conclusion: This questionnaire could guide caregiver interventions and be adapted for use longitudinally, in community cancer settings, and in patients with brain metastases.


Glioblastoma (GBM) is a very aggressive brain cancer. People who have GBM have trouble remembering things and are unable to do things they used to do. These changes can be very hard. Researchers are trying to better understand what it is like for people who take care of people with GBM (or caregivers). In this study, researchers created a new survey for caregivers. The survey included questions about what caregivers see happening in their loved one with GBM. Caregivers said that memory problems were common. Also, when the patient had more problems the caregiver had a harder time, too. Researchers hope to improve the survey and use it in the future for more studies.


Assuntos
Disfunção Cognitiva , Glioblastoma , Adulto , Feminino , Humanos , Cuidadores/psicologia , Glioblastoma/complicações , Glioblastoma/terapia , Glioblastoma/patologia , Projetos Piloto , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/terapia , Inquéritos e Questionários , Qualidade de Vida
5.
J Natl Compr Canc Netw ; 21(1): 12-20, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36634606

RESUMO

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of the following adult CNS cancers: glioma (WHO grade 1, WHO grade 2-3 oligodendroglioma [1p19q codeleted, IDH-mutant], WHO grade 2-4 IDH-mutant astrocytoma, WHO grade 4 glioblastoma), intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastases, leptomeningeal metastases, non-AIDS-related primary CNS lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors. The information contained in the algorithms and principles of management sections in the NCCN Guidelines for CNS Cancers are designed to help clinicians navigate through the complex management of patients with CNS tumors. Several important principles guide surgical management and treatment with radiotherapy and systemic therapy for adults with brain tumors. The NCCN CNS Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding molecular profiling of gliomas.


Assuntos
Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Adulto , Humanos , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/terapia , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Sistema Nervoso Central , Mutação
6.
Neurooncol Adv ; 4(1): vdac029, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35542753

RESUMO

Background: Survivorship for those living with primary CNS cancers begins at diagnosis, continues throughout a person's life, and includes caregivers. Opportunities and challenges exist to advance survivorship care for those living with primary CNS cancers that necessitate stakeholder involvement. Methods: In June 2021, NCI-CONNECT convened a two-day virtual workshop about survivorship care in neuro-oncology. Two expert panels provided key recommendations and five working groups considered critical questions to identify strengths, weaknesses, opportunities, and threats to the advancement of survivorship care and developed recommendations and action items. Results: The following action items emanated from the workshop: seek endorsement of meeting report from stakeholder organizations; address barriers in access to survivorship care and provider reimbursement; advance survivorship research through NIH and private grant support; develop a survivorship tool kit for providers, people living with primary CNS cancers and their caregivers; provide accessible educational content for neuro-oncology, neurology, and oncology community providers about survivorship care in neuro-oncology; and establish core competencies for survivorship care for neuro-oncology providers to be included in training and standardized exams. Conclusions: Action items aim to address access and reimbursement barriers, expand patient and provider education, develop core competencies, and support survivorship research through funding and other supports.

7.
Support Care Cancer ; 30(2): 1365-1375, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34510238

RESUMO

BACKGROUND: Glioblastoma is an incurable disease with a poor prognosis. For caregivers of people with glioblastoma, the burden of care can be high. Patients often present with different clinical characteristics, which may impact caregiver burden in different ways. This study aimed to evaluate associations between patient clinical characteristics and caregiver burden/quality of life (QoL). METHODS: Caregiver-patient dyads were enrolled at 7 academic cancer centers in the United States. Eligible caregiver participants were self-reported as the primary caregiver of an adult living with glioblastoma and completed a caregiver burden survey. Eligible patients were age ≥ 18 years at glioblastoma diagnosis and alive when their respective caregiver entered the study, with the presence of cognitive dysfunction confirmed by the caregiver. Data were analyzed with descriptive statistics and multivariable analyses. RESULTS: The final cohort included 167 dyads. Poor patient performance status resulted in patient difficulty with mental tasks, more caregiving tasks, and increased caregiving time. Language problems were reported in patients with left-sided lesions. Patient confusion was negatively associated with all caregiver domains: emotional health, social health, general health, ability to work, confidence in finances, and overall QoL. Better caregiver QoL was observed in patients with frontal lobe lesions versus non-frontal lobe lesions. CONCLUSION: This study reinforced that patient performance status is a critical clinical factor that significantly affects caregiver burden, caregiving tasks, and caregiver time. Additionally, patient confusion affects multiple facets of caregiver burden/QoL. These results could be used to support guided intervention for caregiver support, customized to the patient experience.


Assuntos
Glioblastoma , Qualidade de Vida , Adolescente , Adulto , Sobrecarga do Cuidador , Cuidadores , Efeitos Psicossociais da Doença , Glioblastoma/terapia , Humanos , Inquéritos e Questionários
9.
Neurooncol Pract ; 8(6): 662-673, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34777835

RESUMO

BACKGROUND: The development of brain metastases (BM) is one of the most feared complications of cancer due to the substantial neurocognitive morbidity and a grim prognosis. In the past decade, targeted therapies and checkpoint inhibitors have demonstrated promising intracranial response rates for tumors of multiple histologies. As overall survival for these patients improves, there is a growing need to identify issues surrounding patient survivorship and to standardize physician practice patterns for these patients. To date, there has not been an adequate study to specifically explore these questions of survivorship and practice standardization for patients with advanced cancer and BM. METHODS: Here, we present results from a cross-sectional survey in which we analyze responses from 237 patients, 209 caregivers, and 239 physicians to identify areas of improvement in the clinical care of BM. RESULTS: In comparing physician and patient/caregiver responses, we found a disparity in the perceived discussion of topics pertaining to important aspects of BM clinical care. We identified variability in practice patterns for this patient population between private practice and academic physicians. Many physicians continue to have patients with BM excluded from clinical trials. Finally, we obtained patient/physician recommendations on high-yield areas for federal funding to improve patient quality of life. CONCLUSION: By identifying potential areas of unmet need, we anticipate this wealth of actionable information will translate into tangible benefits for both patients and caregivers. Future studies are needed to validate our findings.

10.
J Natl Compr Canc Netw ; 18(11): 1537-1570, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33152694

RESUMO

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of adult CNS cancers ranging from noninvasive and surgically curable pilocytic astrocytomas to metastatic brain disease. The involvement of an interdisciplinary team, including neurosurgeons, radiation therapists, oncologists, neurologists, and neuroradiologists, is a key factor in the appropriate management of CNS cancers. Integrated histopathologic and molecular characterization of brain tumors such as gliomas should be standard practice. This article describes NCCN Guidelines recommendations for WHO grade I, II, III, and IV gliomas. Treatment of brain metastases, the most common intracranial tumors in adults, is also described.


Assuntos
Astrocitoma , Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Glioma , Adulto , Astrocitoma/diagnóstico , Astrocitoma/terapia , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/terapia , Sistema Nervoso Central , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/terapia , Glioma/diagnóstico , Glioma/terapia , Humanos , Guias de Prática Clínica como Assunto
11.
Neurooncol Adv ; 2(1): vdaa097, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33005896

RESUMO

BACKGROUND: Medulloblastoma (MB) is a rare brain tumor occurring more frequently in children in whom research has been primarily focused. Treatment recommendations in adults are mainly based on retrospective data and pediatric experience; however, molecular features and treatment tolerance differ between the 2 age groups. In adults, prognostic tools are suboptimal, late recurrences are typical, and long-term sequelae remain understudied. Treatment has not adapted to molecular classification advances; thus, the survival rate of adult MB has not improved. METHODS: In 2017, the National Cancer Institute (NCI) received support from the Cancer Moonshot℠ to address the challenges and unmet needs of adults with rare central nervous system tumors through NCI-CONNECT, a program that creates partnerships among patients, health care professionals, researchers, and advocacy organizations. On November 25, 2019, NCI-CONNECT convened leading clinicians and scientists in a workshop to review advances in research, share scientific insights, and discuss clinical challenges in adult MB. RESULTS: Working groups identified unmet needs in clinical trial design, tissue acquisition and testing, tumor modeling, and measurement of clinical outcomes. CONCLUSIONS: Participants identified opportunities for collaboration; discussed plans to create a working group of clinicians, researchers, and patient advocates; and developed specific action items to expedite progress in adult MB.

12.
Neurooncol Adv ; 2(1): vdaa086, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32793887

RESUMO

BACKGROUND: We aimed to explore gaps in the care of meningioma patients that could improve quality of care by better understanding symptoms experienced by patients at various stages of treatment, and afterwards. METHODS: A novel 19-item self-administered questionnaire was provided for patients with meningiomas to complete by the American Brain Tumor Association (ABTA) over a 3-month period. RESULTS: A total of 1852 unique respondents were included. Nearly one-third of all respondents felt they received insufficient information about meningiomas at initial diagnosis (N = 607, 32.9%) and 28.8% (N = 530) believed they received insufficient information about treatment options. In fact, 34.5% of respondents received the majority of their information from the internet and nonhealthcare professionals. The most common concerns after initial diagnosis were risks associated with surgery and/or treatment (36.5%) followed by how the tumor would impact daily life (25%) and the risk of tumor recurrence (12.4%). Respondents indicated that a list of resources available for patients with meningiomas (N = 597, 32.3%) would have been most beneficial in regards to their disease experience after their initial diagnosis. Moreover, we found that a substantial proportion of patients continued to report symptoms long after treatment, with fatigue being the most common compared to before treatment (38.2% vs. 57.7%, χ 2 = 128, P < .001). CONCLUSIONS: Patients with meningiomas exhibit symptoms that continue well after treatment with fatigue and cognitive impairments as the most bothersome. Moreover, patients report key communication gaps that can be addressed to improve their disease experience and care.

13.
Health Expect ; 23(1): 41-51, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31722131

RESUMO

CONTEXT: Patient-reported outcomes (PROs) are used in parallel with clinical evidence to inform decisions made by industry, clinicians, regulators, health technology assessment bodies and other health-care decision-makers. In addition, PRO data can also guide shared decision making and individual patient choice. Yet, the quality of many PROs in cancer clinical trials is suboptimal and requires improvement to add value to health care and policy decision making. OBJECTIVE: To show how the integration of the patient and/or patient advocate at all stages of PRO development can help to realize the full potential of PROs. METHODS: We examined the literature to show that the patient voice is often absent from the planning and implementation of PROs in cancer clinical trials. Good practice examples from the literature were combined with guideline recommendations, training or educational resources, and our own experience to create detailed practical steps for the inclusion of patients and/or patient advocates throughout PRO development. RESULTS: Patient or patient advocates can play an active role in shaping PROs that are meaningful to the patient. They can contribute to content, choice of medium and implementation in a way that may support PRO completion and minimize missing data. Patients and their advocates can work to ensure PRO findings are disseminated appropriately in a way that is accessible to patients. CONCLUSION: This practical guidance aims to optimize PRO development and implementation in clinical trials, resulting in robust, relevant data that reflect the patient experience and that support decisions made by all stakeholders involved in research and health care.


Assuntos
Ensaios Clínicos como Assunto , Neoplasias/terapia , Defesa do Paciente , Participação do Paciente , Medidas de Resultados Relatados pelo Paciente , Projetos de Pesquisa , Humanos , Avaliação da Tecnologia Biomédica
14.
Neuro Oncol ; 21(9): 1100-1117, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31175826

RESUMO

Many factors contribute to the poor survival of malignant brain tumor patients, some of which are not easily remedied. However, one contributor to the lack of progress that may be modifiable is poor clinical trial accrual. Surveys of brain tumor patients and neuro-oncology providers suggest that clinicians do a poor job of discussing clinical trials with patients and referring patients for clinical trials. Yet, data from the Cancer Action Network of the American Cancer Society suggest that most eligible oncology patients asked to enroll on a clinical trial will agree to do so. To this end, the Society for Neuro-Oncology (SNO) in collaboration with the Response Assessment in Neuro-Oncology (RANO) Working Group, patient advocacy groups, clinical trial cooperative groups, including the Adult Brain Tumor Consortium (ABTC), and other partners are working together with the intent to double clinical trial accrual over the next 5 years. Here we describe the factors contributing to poor clinical trial accrual in neuro-oncology and offer possible solutions.


Assuntos
Atitude Frente a Saúde , Neoplasias Encefálicas/terapia , Tomada de Decisões , Oncologistas , Seleção de Pacientes , Relações Médico-Paciente , Encaminhamento e Consulta , Conscientização , Escolaridade , Disparidades em Assistência à Saúde , Humanos , Viagem
15.
J Natl Compr Canc Netw ; 15(11): 1331-1345, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29118226

RESUMO

For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options. Research to identify molecular changes that underlie glioma progression has led to the discovery of molecular features that have greater diagnostic and prognostic value than histology. Analyses of these molecular markers across populations from randomized clinical trials have shown that some of these markers are also predictive of response to specific types of treatment, which has prompted significant changes to the recommended treatment options for grade III (anaplastic) gliomas.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Neoplasias do Sistema Nervoso Central/diagnóstico , Glioma/diagnóstico , Sistema Nervoso/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/normas , Neoplasias do Sistema Nervoso Central/classificação , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/terapia , Terapia Combinada/métodos , Terapia Combinada/normas , Glioma/classificação , Glioma/patologia , Glioma/terapia , Humanos , Terapia Neoadjuvante/métodos , Terapia Neoadjuvante/normas , Gradação de Tumores , Prognóstico , Radioterapia/métodos , Radioterapia/normas
16.
Cancer Res ; 74(14): 3959-70, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24830723

RESUMO

The cyclin D1 gene encodes the regulatory subunit of a holoenyzme that phosphorylates the retinoblastoma protein (pRb) and nuclear respiratory factor (NRF1) proteins. The abundance of cyclin D1 determines estrogen-dependent gene expression in the mammary gland of mice. Using estradiol (E2) and an E2-dendrimer conjugate that is excluded from the nucleus, we demonstrate that E2 delays the DNA damage response (DDR) via an extranuclear mechanism. The E2-induced DDR required extranuclear cyclin D1, which bound ERα at the cytoplasmic membrane and augmented AKT phosphorylation (Ser473) and γH2AX foci formation. In the nucleus, E2 inhibited, whereas cyclin D1 enhanced homology-directed DNA repair. Cyclin D1 was recruited to γH2AX foci by E2 and induced Rad51 expression. Cyclin D1 governs an essential role in the E2-dependent DNA damage response via a novel extranuclear function. The dissociable cytoplasmic function to delay the E2-mediated DDR together with the nuclear enhancement of DNA repair uncovers a novel extranuclear function of cyclin D1 that may contribute to the role of E2 in breast tumorigenesis.


Assuntos
Ciclina D1/genética , Reparo do DNA , Estrogênios/metabolismo , Transdução de Sinais , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Cromatina/metabolismo , Ciclina D1/metabolismo , Dano ao DNA , Estradiol/metabolismo , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Camundongos , Ligação Proteica , Interferência de RNA , Rad51 Recombinase/metabolismo
17.
J Biol Chem ; 286(3): 2132-42, 2011 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-20937839

RESUMO

The cell fate determination factor Dachshund was cloned as a dominant inhibitor of the hyperactive epidermal growth factor receptor ellipse. The expression of Dachshund is lost in human breast cancer associated with poor prognosis. Breast tumor-initiating cells (TIC) may contribute to tumor progression and therapy resistance. Here, endogenous DACH1 was reduced in breast cancer cell lines with high expression of TIC markers and in patient samples of the basal breast cancer phenotype. Re-expression of DACH1 reduced new tumor formation in serial transplantations in vivo, reduced mammosphere formation, and reduced the proportion of CD44(high)/CD24(low) breast tumor cells. Conversely, lentiviral shRNA to DACH1 increased the breast (B)TIC population. Genome-wide expression studies of mammary tumors demonstrated DACH1 repressed a molecular signature associated with stem cells (SOX2, Nanog, and KLF4) and genome-wide ChIP-seq analysis identified DACH1 binding to the promoter of the Nanog, KLF4, and Lin28 genes. KLF4/c-Myc and Oct4/Sox2 antagonized DACH1 repression of BTIC. Mechanistic studies demonstrated DACH1 directly repressed the Nanog and Sox2 promoters via a conserved domain. Endogenous DACH1 regulates BTIC in vitro and in vivo.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Desdiferenciação Celular , Proteínas do Olho/metabolismo , Células-Tronco Neoplásicas/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição ARNTL/genética , Animais , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Antígeno CD24/genética , Antígeno CD24/metabolismo , Linhagem Celular Tumoral , Proteínas do Olho/genética , Feminino , Estudo de Associação Genômica Ampla , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Camundongos , Camundongos Nus , Proteína Homeobox Nanog , Transplante de Neoplasias , Células-Tronco Neoplásicas/patologia , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Fatores de Transcrição/genética
18.
Cancer Res ; 70(24): 10464-73, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21159656

RESUMO

The role of mammary epithelial cell (MEC) NF-κB in tumor progression in vivo is unknown, as murine NF-κB components and kinases either are required for murine survival or interfere with normal mammary gland development. As NF-κB inhibitors block both tumor-associated macrophages (TAM) and MEC NF-κB, the importance of MEC NF-κB to tumor progression in vivo remained to be determined. Herein, an MEC-targeted inducible transgenic inhibitor of NF-κB (IκBαSR) was developed in ErbB2 mammary oncomice. Inducible suppression of NF-κB in the adult mammary epithelium delayed the onset and number of new tumors. Within similar sized breast tumors, TAM and tumor neoangiogenesis was reduced. Coculture experiments demonstrated MEC NF-κB enhanced TAM recruitment. Genome-wide expression and proteomic analysis showed that IκBαSR inhibited tumor stem cell pathways. IκBαSR inhibited breast tumor stem cell markers in transgenic tumors, reduced stem cell expansion in vitro, and repressed expression of Nanog and Sox2 in vivo and in vitro. MEC NF-κB contributes to mammary tumorigenesis. As we show that NF-κB contributes to expansion of breast tumor stem cells and heterotypic signals that enhance TAM and vasculogenesis, these processes may contribute to NF-κB-dependent mammary tumorigenesis.


Assuntos
Transformação Celular Neoplásica/patologia , Neoplasias Mamárias Experimentais/patologia , NF-kappa B/metabolismo , Células-Tronco Neoplásicas/patologia , Animais , Processos de Crescimento Celular/fisiologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal , Feminino , Proteínas I-kappa B/biossíntese , Proteínas I-kappa B/genética , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Camundongos Transgênicos , Inibidor de NF-kappaB alfa , NF-kappa B/antagonistas & inibidores , Células-Tronco Neoplásicas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor ErbB-2/biossíntese , Transfecção
19.
Proc Natl Acad Sci U S A ; 107(18): 8231-6, 2010 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-20406904

RESUMO

microRNAs are thought to regulate tumor progression and invasion via direct interaction with target genes within cells. Here the microRNA17/20 cluster is shown to govern cellular migration and invasion of nearby cells via heterotypic secreted signals. microRNA17/20 abundance is reduced in highly invasive breast cancer cell lines and node-positive breast cancer specimens. Cell-conditioned medium from microRNA17/20-overexpressing noninvasive breast cancer cell MCF7 was sufficient to inhibit MDA-MB-231 cell migration and invasion through inhibiting secretion of a subset of cytokines, and suppressing plasminogen activation via inhibition of the secreted plasminogen activators (cytokeratin 8 and alpha-enolase). microRNA17/20 directly repressed IL-8 by targeting its 3' UTR, and inhibited cytokeratin 8 via the cell cycle control protein cyclin D1. At variance with prior studies, these results demonstrated a unique mechanism of how the altered microRNA17/20 expression regulates cellular secretion and tumor microenvironment to control migration and invasion of neighboring cells in breast cancer. These findings not only reveal an antiinvasive function of miR-17/20 in breast cancer, but also identify a heterotypic secreted signal that mediates the microRNA regulation of tumor metastasis.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , MicroRNAs/genética , Transdução de Sinais , Regiões 3' não Traduzidas , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Ativação Enzimática , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucina-8/genética , Interleucina-8/metabolismo , Invasividade Neoplásica , Metástase Neoplásica , Plasminogênio/metabolismo , Ligação Proteica
20.
J Biol Chem ; 285(11): 8218-26, 2010 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-20053993

RESUMO

The molecular mechanisms governing breast tumor cellular self-renewal contribute to breast cancer progression and therapeutic resistance. The ErbB2 oncogene is overexpressed in approximately 30% of human breast cancers. c-Jun, the first cellular proto-oncogene, is overexpressed in human breast cancer. However, the role of endogenous c-Jun in mammary tumor progression is unknown. Herein, transgenic mice expressing the mammary gland-targeted ErbB2 oncogene were crossed with c-jun(f/f) transgenic mice to determine the role of endogenous c-Jun in mammary tumor invasion and stem cell function. The excision of c-jun by Cre recombinase reduced cellular migration, invasion, and mammosphere formation of ErbB2-induced mammary tumors. Proteomic analysis identified a subset of secreted proteins (stem cell factor (SCF) and CCL5) induced by ErbB2 expression that were dependent upon endogenous c-Jun expression. SCF and CCL5 were identified as transcriptionally induced by c-Jun. CCL5 rescued the c-Jun-deficient breast tumor cellular invasion phenotype. SCF rescued the c-Jun-deficient mammosphere production. Endogenous c-Jun thus contributes to ErbB2-induced mammary tumor cell invasion and self-renewal.


Assuntos
Neoplasias da Mama/patologia , Neoplasias da Mama/fisiopatologia , Regulação Neoplásica da Expressão Gênica , Proteínas Proto-Oncogênicas c-jun/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , Animais , Neoplasias da Mama/genética , Divisão Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Quimiocina CCL5/metabolismo , Células Epiteliais/patologia , Células Epiteliais/fisiologia , Feminino , Humanos , Camundongos , Camundongos Transgênicos , Invasividade Neoplásica/patologia , Invasividade Neoplásica/fisiopatologia , Fenótipo , Proto-Oncogene Mas , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Fator de Células-Tronco/metabolismo
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