RESUMO
Some transcripts that are not translated into proteins can be encoded by the mammalian genome. Long noncoding RNAs (lncRNAs) are noncoding RNAs that can function as decoys, scaffolds, and enhancer RNAs and can regulate other molecules, including microRNAs. Therefore, it is essential that we obtain a better understanding of the regulatory mechanisms of lncRNAs. In cancer, lncRNAs function through several mechanisms, including important biological pathways, and the abnormal expression of lncRNAs contributes to breast cancer (BC) initiation and progression. BC is the most common type of cancer among women worldwide and has a high mortality rate. Genetic and epigenetic alterations that can be regulated by lncRNAs may be related to early events of BC progression. Ductal carcinoma in situ (DCIS) is a noninvasive BC that is considered an important preinvasive BC early event because it can progress to invasive BC. Therefore, the identification of predictive biomarkers of DCIS-invasive BC progression has become increasingly important in an attempt to optimize the treatment and quality of life of patients. In this context, this review will address the current knowledge about the role of lncRNAs in DCIS and their potential contribution to the progression of DCIS to invasive BC.
Assuntos
Neoplasias da Mama , Carcinoma in Situ , Carcinoma Intraductal não Infiltrante , RNA Longo não Codificante , Animais , Humanos , Feminino , Carcinoma Intraductal não Infiltrante/genética , Carcinoma Intraductal não Infiltrante/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Qualidade de Vida , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma in Situ/genética , Epigênese Genética , Mamíferos/metabolismoRESUMO
Long non-coding RNAs are increasingly being recognized as cancer biomarkers in various malignancies, acting as either tumor suppressors or oncogenes. The long non-coding MALINC1 intergenic RNA was identified as significantly upregulated in breast ductal carcinoma in situ. The aim of this study was to characterize MALINC1 expression, localization, and phenotypic and molecular effects in non-invasive and invasive breast cancer cells. We determined that MALINC1 is an estrogen-estrogen receptor-modulated lncRNA enriched in the cytoplasmic fraction of luminal A/B breast cancer cells that is associated with worse overall survival in patients with primary invasive breast carcinomas. Transcriptomic studies in normal and DCIS cells identified the main signaling pathways modulated by MALINC1, which mainly involve bioprocesses related to innate and adaptive immune responses, extracellular matrix remodeling, cell adhesion, and activation of AP-1 signaling pathway. We determined that MALINC1 induces premalignant phenotypic changes by increasing cell migration in normal breast cells. Moreover, high MALINC1 expression in invasive carcinomas was associated with a pro-tumorigenic immune environment and a favorable predicted response to immunotherapy both in luminal and basal-like subtypes compared with low-MALINC1-expression tumors. We conclude that MALINC1 behaves as an oncogenic and immune-related lncRNA involved with early-stage breast cancer progression.
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The long-non-coding HOX transcript antisense intergenic RNA (HOTAIR) was identified as significantly upregulated in breast ductal carcinoma in situ (DCIS). The aim of this study was to characterize the phenotypic effects and signaling pathways modulated by HOTAIR in early-stage breast cancer progression. We determined that HOTAIR induces premalignant phenotypic changes by increasing cell proliferation, migration, invasion and in vivo growth in normal and DCIS breast cell lines. Transcriptomic studies (RNA-seq) identified the main signaling pathways modulated by HOTAIR which include bioprocesses related to epithelial to mesenchymal transition, cell migration, extracellular matrix remodeling and activation of several signaling pathways (HIF1A, AP1 and FGFR). Similar pathways were identified as activated in primary invasive breast carcinomas with HOTAIR over-expression. We conclude that HOTAIR over-expression behaves as a positive regulator of cell growth and migration both in normal and DCIS breast cells involved with early-stage breast cancer progression.
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Long intergenic non-protein coding RNA 885 (LINC00885) was identified as significantly upregulated in breast ductal carcinoma in situ (DCIS). The aim of this study was to characterize the phenotypic effects and signaling pathways modulated by LINC00885 in non-invasive and invasive breast cancer models. We determined that LINC00885 induces premalignant phenotypic changes by increasing cell proliferation, motility, migration and altering 3D growth in normal and DCIS breast cell lines. Transcriptomic studies (RNA-seq) identified the main signaling pathways modulated by LINC00885, which include bioprocesses related to TP53 signaling pathway and proliferative signatures such as activation of EREG, EGFR and FOXM1 pathways. LINC00885 silencing in breast cancer lines overexpressing this lncRNA leads to downregulation of proliferation related transcripts such as EREG, CMYC, CCND1 and to significant decrease in cell migration and motility. TCGA-BRCA data analyses show an association between high LINC00885 expression and worse overall survival in patients with primary invasive breast carcinomas (p = 0.024), suggesting that the pro-tumorigenic effects of LINC00885 overexpression persist post-invasion. We conclude that LINC00885 behaves as a positive regulator of cell growth both in normal and DCIS breast cells possibly operating as a ceRNA and representing a novel oncogenic lncRNA associated with early stage breast cancer progression.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carcinoma Intraductal não Infiltrante/genética , Carcinoma Intraductal não Infiltrante/metabolismo , Progressão da Doença , Oncogenes , RNA Longo não Codificante/genética , Neoplasias da Mama/patologia , Carcinogênese/genética , Carcinoma Intraductal não Infiltrante/patologia , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Células MCF-7 , Invasividade Neoplásica/genética , Estadiamento de Neoplasias , Interferência de RNA , RNA Longo não Codificante/metabolismo , Transcriptoma , Regulação para Cima/genéticaRESUMO
Objective: To verify data-coding accuracy for ductal carcinoma in situ at the Goiânia population-based cancer registry in the Brazilian state of Goiás. Methods: Ecological time series analysis of cases coded as ductal carcinoma in situ in the state cancer database (ONCOSIS), considering data from the Goiânia population-based cancer registry, from 1994 to 2010. Results: Of 376 cases originally coded as ductal carcinoma in situ, 115 were excluded following a review of the pathology reports. These exclusions referred to cases of lobular carcinoma in situ (n=21), Paget's disease (n=4), invasive carcinoma (n=08), ductal carcinoma in situ associated with invasive carcinoma (n=14), microinvasive carcinoma (n=21), records on non-residents in Goiânia, and duplicated data (n=46). Conclusion: Many cases needed recoding and, as a consequence, altered the initial database. Standardizing pathology reports and training data collection staff are crucial steps to avoid omissions and errors when transcribing cases of ductal carcinoma in situ in a population-based cancer registry database.
Objetivo: Verificar a acurácia da codificação dos dados de carcinoma ductal in situ dentro do Registro de Câncer de Base Populacional de Goiânia, Goiás - Brasil. Métodos: Estudo ecológico de série temporal de casos codificados como carcinoma in situ da mama, pelo programa (ONCOSIS) do Registro de Câncer de Base Populacional de Goiânia, entre 1994 e 2010. Posteriormente realizouse busca individual dos laudos histopatológicos de CDIS. Resultados: De 376 casos de CDIS, foram excluídos 115 casos após a revisão dos laudos anatomopatológicosas. As exclusões referem-se a carcinoma lobular in situ (21), Doença de Paget (4), carcinoma invasor (08); CDIS associado a carcinoma invasor (14); microinvasor (21), pacientes com endereço fora de Goiânia e dados duplicados (46). Conclusão: Há um grande número de casos que precisam ser recodificados, alterando o banco inicial. A padronização de laudos e o treinamento dos coletadores são etapas importantes para que não haja informações desconhecidas ao transcrever o CDIS para as fichas do RCBP.
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BACKGROUND: While the roles of hypofractionated (HFxn) radiotherapy and lumpectomy boost in the adjuvant management of invasive breast cancer are supported by the results of clinical trials, randomized data supporting their use for ductal carcinoma in situ (DCIS) are forthcoming. We sought to evaluate current national trends and identify factors associated with HFxn and boost usage using the National Cancer Database. PATIENTS AND METHODS: We queried the National Cancer Database for women diagnosed with DCIS from 2004 to 2014 undergoing external beam radiotherapy after breast conservation surgery. Patients were categorized as receiving either conventional fractionation (CFxn) or HFxn and as either receiving or not receiving a boost. Multiple logistic regression was performed to identify demographic, clinical, and treatment factor associations. RESULTS: A total of 101,615 women were identified, with 87,641 (86.2%) receiving CFxn, 13,974 (13.8%) receiving HFxn, and most patients in each group (84.9% and 57.7%, respectively) receiving a boost. Implementation of HFxn increased from 4.3% in 2004 to 33.0% in 2014, and the use of a boost declined from 83.3% to 74.6%. HFxn receipt was independently associated with later year of diagnosis, older age, higher income, greater distance from treatment facility, greater facility volume, academic facility type, Western residence, smaller lesions, and nonreceipt of a boost. Factors associated with boost receipt included earlier year of diagnosis, younger age, higher income, community facility type, adverse pathologic features, and nonreceipt of HFxn. CONCLUSION: Although CFxn with a boost remains the most common external beam radiotherapy strategy for DCIS, implementation of HFxn without a boost appears to be increasing. Practice patterns at present seem to be driven by guidelines for invasive breast cancer and nonclinical factors.
Assuntos
Neoplasias da Mama/terapia , Carcinoma Intraductal não Infiltrante/terapia , Padrões de Prática Médica/estatística & dados numéricos , Hipofracionamento da Dose de Radiação/normas , Fatores Etários , Idoso , Feminino , Fidelidade a Diretrizes , Humanos , Mastectomia Segmentar , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Padrões de Prática Médica/normas , Radioterapia Adjuvante/métodos , Radioterapia Adjuvante/normas , Radioterapia Adjuvante/estatística & dados numéricos , Fatores Socioeconômicos , Estados UnidosRESUMO
BACKGROUND: The purpose of the study was to identify the effect of final surgical margin (SM) status and re-excision on outcomes in patients with ductal carcinoma in situ (DCIS) who underwent breast conservation therapy (BCT). PATIENTS AND METHODS: The study population consisted of women diagnosed with DCIS who underwent BCT between 1989 and 2014. All women received adjuvant whole breast radiation and a boost. The primary end point was local control (LC). Final SMs were defined according to margin width: negative SM was defined as > 2 mm, close SM was defined as > 0 to ≤ 2 mm, and a positive SM was defined as tumor on ink. The Cox proportional hazards model was used to determine predictors of outcomes on multivariable analysis. Actuarial incidence of LC was estimated using the Kaplan-Meier method. RESULTS: A total of 498 patients were included; 400 patients had a final negative SM, 87 had a close SM, and 11 had a positive SM. A total of 172 patients received adjuvant hormonal therapy, 265 patients required ≥ 1 re-excision. Patients with positive or close SMs were more likely to receive a radiation dose > 60 Gy (P < .001) and undergo re-excision (P < .01). The 10-year LC rates were not significantly different between patients with a negative (93.5%), close (91.8%), or positive (100%) SM (P = .57). There was no difference in LC in patients who underwent re-excision for initial close or positive SMs (P = .55). CONCLUSION: This single-institution experience showed that risks of local recurrence remain poorly characterized. Re-excision and whole breast radiation with boost resulted in excellent LC for women with DCIS. Trials aimed at personalized deintensified local therapy are warranted.
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Neoplasias da Mama/cirurgia , Carcinoma Intraductal não Infiltrante/cirurgia , Margens de Excisão , Mastectomia Segmentar , Recidiva Local de Neoplasia/prevenção & controle , Reoperação , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Carcinoma Intraductal não Infiltrante/mortalidade , Carcinoma Intraductal não Infiltrante/patologia , Carcinoma Intraductal não Infiltrante/radioterapia , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Radioterapia Adjuvante/métodos , Resultado do TratamentoRESUMO
The spread of mammographic screening programmes around the world, including in developing countries, has substantially contributed to the diagnosis of small non-palpable lesions, which has increased the detection rate of DCIS (ductal carcinoma in situ). DCIS is heterogeneous in several ways, such as its clinical presentation, morphology and genomic profile. Excellent outcomes have been reported; however, many questions remain unanswered. For example, which patients groups are overtreated and could instead benefit from minimal intervention and which patient groups require a more traditional multidisciplinary approach. The development of a comprehensive integrated analysis that includes the radiological, morphological and genetic aspects of DCIS is necessary to answer these questions. This review focuses on discussing the significant findings about the morphological and molecular features of DCIS and its progression that have helped to uncover the biological and genetic heterogeneity of this disease. The knowledge gained in recent years might allow the development of tailored clinical management for women with DCIS in the future.