Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 121
Filtrar
1.
Front Oncol ; 11: 562378, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34676156

RESUMO

Background: LncRNAs have been shown to play critical roles in regulating tumorigenesis and tumor progression. Using LncRNAs to predict prognosis and therapeutic response to cancer treatment has been caused for concern, but the predictive value of lncRNAs remains to be explored and underlying mechanisms have not been completely understood. Methods: The Linc01315 expression level was detected in 282 breast cancer tissues by using quantitative RT-PCR. The association between Linc01315 expression level and clinicopathological features of these breast cancer patients was further analyzed. Multiple regression analysis was used to evaluate Linc01315 predictive value of patients' prognosis. Results: Our study revealed that Linc01315 expression level was significantly correlated with vessel invasion (P = 0.028) and tumor subtype (P = 0.039). The Kaplan-Meier survival curves demonstrated that patients with lower Linc01315 expression level had significantly longer disease free survival (DFS) (P = 0.002) and overall survival (OS) (P=0.019). Multiple regression analysis showed that Linc01315 level could be an independent predictive factor for DFS (hazards ratio = 0.613, 95% confidence interval = 0.375-1.003; P = 0.049) and OS (hazards ratio = 0.439, 95% confidence interval = 0.228-0.845; P = 0.014). Further analysis showed that low Linc01315 level patients with endocrine therapy could benefit patients DFS (P=0.037) and OS (P=0.025). Conclusion: Our results demonstrate that Linc01315 expression level is significantly correlated with breast cancer patients' prognosis. Linc01315 may represent an independent prognostic marker and therapeutic target in breast cancer.

2.
Cancer Manag Res ; 13: 5763-5774, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34305410

RESUMO

Background: Triple-negative breast cancers (TNBC), comprising about 20% of breast cancers, have a poor prognosis. Currently, there is no effective target therapy for TNBC. LncRNA TUSC7 has been identified as a tumor suppressor in osteosarcoma and colorectal cancer. In this study, we investigated the clinical significance and the biological function of TUSC7 in breast cancer. Methods: We retrospectively evaluated the expression level and clinical significance of TUSC7 in 90 paired breast cancer tissues and normal tissues. The proliferation, migration, and invasion assays were performed to investigate the biological function of TUSC7 in breast cancer. Finally, microarray, a luciferase reporter assay, and quantitative real-time polymerase chain reaction (qPCR) were used to explore the potential underlying mechanism of tumor suppressor role of TUSC7. Results: Low TUSC7 expression was found to be an independent prognostic factor of poor overall survival (OS) in TNBC patients. Ectopic expression of TUSC7 inhibited tumor cell growth both in vitro and in vivo. TUSC7 overexpression significantly promoted the sensitivity of MDA-MB-468 cells to paclitaxel and carboplatin. In terms of the mechanism, TUSC7 might perform its biological function through binding with miR-1224-3P and regulating its expression level. Besides, genes in cell cycle pathways, such as BUB3 (budding uninhibited by benzimidazoles 3) and TGF-ß (targeting transforming growth factor ß) pathways were downregulated, and genes involved in the MAPK (mitogen-activated protein kinase) (TGFBR2, transforming growth factor-beta receptor 2), PI3K-AKT (phosphoinositide 3-kinase- AKT serine/threonine kinase 1) and NF-κB (nuclear factor-kappa B subunit) pathways were upregulated in TUSC7 knockdown MDA-MB-231 cells. Conclusion: The low TUSC7 expression is an independent prognostic factor of poor OS of TNBC patients. TUSC7 might inhibit breast cancer cell growth and metastasis both in vitro and vivo through binding with miR-1224-3P and regulating MAPK, PI3K/AKT, and NF-κB signaling pathways.

3.
Nat Commun ; 12(1): 4413, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285210

RESUMO

Enhanced neovasculogenesis, especially vasculogenic mimicry (VM), contributes to the development of triple-negative breast cancer (TNBC). Breast tumor-initiating cells (BTICs) are involved in forming VM; however, the specific VM-forming BTIC population and the regulatory mechanisms remain undefined. We find that tumor endothelial marker 8 (TEM8) is abundantly expressed in TNBC and serves as a marker for VM-forming BTICs. Mechanistically, TEM8 increases active RhoC level and induces ROCK1-mediated phosphorylation of SMAD5, in a cascade essential for promoting stemness and VM capacity of breast cancer cells. ASB10, an estrogen receptor ERα trans-activated E3 ligase, ubiquitylates TEM8 for degradation, and its deficiency in TNBC resulted in a high homeostatic level of TEM8. In this work, we identify TEM8 as a functional marker for VM-forming BTICs in TNBC, providing a target for the development of effective therapies against TNBC targeting both BTIC self-renewal and neovasculogenesis simultaneously.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas dos Microfilamentos/metabolismo , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/patologia , Receptores de Superfície Celular/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Mama/patologia , Mama/cirurgia , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Linhagem Celular Tumoral , Autorrenovação Celular/efeitos dos fármacos , Feminino , Humanos , Mastectomia , Camundongos , Proteínas dos Microfilamentos/antagonistas & inibidores , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Receptores de Superfície Celular/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/irrigação sanguínea , Neoplasias de Mama Triplo Negativas/terapia , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Clin Oncol ; 38(34): 3987-3998, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32954927

RESUMO

PURPOSE: Many patients with HR+, HER2- early breast cancer (EBC) will not experience recurrence or have distant recurrence with currently available standard therapies. However, up to 30% of patients with high-risk clinical and/or pathologic features may experience distant recurrence, many in the first few years. Superior treatment options are needed to prevent early recurrence and development of metastases for this group of patients. Abemaciclib is an oral, continuously dosed, CDK4/6 inhibitor approved for HR+, HER2- advanced breast cancer (ABC). Efficacy and safety of abemaciclib in ABC supported evaluation in the adjuvant setting. METHODS: This open-label, phase III study included patients with HR+, HER2-, high-risk EBC, who had surgery and, as indicated, radiotherapy and/or adjuvant/neoadjuvant chemotherapy. Patients with four or more positive nodes, or one to three nodes and either tumor size ≥ 5 cm, histologic grade 3, or central Ki-67 ≥ 20%, were eligible and randomly assigned (1:1) to standard-of-care adjuvant endocrine therapy (ET) with or without abemaciclib (150 mg twice daily for 2 years). The primary end point was invasive disease-free survival (IDFS), and secondary end points included distant relapse-free survival, overall survival, and safety. RESULTS: At a preplanned efficacy interim analysis, among 5,637 randomly assigned patients, 323 IDFS events were observed in the intent-to-treat population. Abemaciclib plus ET demonstrated superior IDFS versus ET alone (P = .01; hazard ratio, 0.75; 95% CI, 0.60 to 0.93), with 2-year IDFS rates of 92.2% versus 88.7%, respectively. Safety data were consistent with the known safety profile of abemaciclib. CONCLUSION: Abemaciclib when combined with ET is the first CDK4/6 inhibitor to demonstrate a significant improvement in IDFS in patients with HR+, HER2- node-positive EBC at high risk of early recurrence.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminopiridinas/administração & dosagem , Aminopiridinas/efeitos adversos , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Adulto Jovem
5.
Theranostics ; 10(12): 5242-5258, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32373210

RESUMO

Rationale: Chromodomain Y-like 2 (CDYL2) is a member of the CDY gene family involved in spermatogenesis, but its role in human cancer has not been reported. Analyses of publicly available databases demonstrate that CDYL2 is abundantly expressed in breast tumors. However, whether CDYL2 is involved in breast cancer progression remains unknown. Methods: Quantitative real-time PCR and immunoblotting assays were used to determine the expression levels of CDYL2 transcript variants in breast cancer cell lines and primary breast tumors. The effect of CDYL2 transcript variants on the malignant phenotypes of breast cancer cells was examined through in vitro and in vivo assays. Immunofluorescent staining, RNA-seq, ATAC-seq, and ChIP-qPCR were used to investigate the underlying mechanisms behind the aforementioned observations. Results: Here we show that CDYL2 generated four transcript variants, named CDYL2a-CDYL2d. CDYL2a and CDYL2b were the predominant variants expressed in breast cancer cell lines and breast tumors and exerted strikingly discrete functions in breast cancer growth and metastasis. CDYL2a was upregulated in the majority of the breast cancer cell lines and tumors, and promoted breast cancer cell proliferation, colony formation in vitro, and tumorigenesis in xenografts. In contrast, CDYL2b was mainly expressed in luminal- and HER2-positive types of breast cancer cell lines and tumors, and suppressed the migratory, invasive, and metastatic potential of breast cancer cells in vitro and in vivo. Mechanistically, CDYL2a partially localized to SC35-positive nuclear speckles and promoted alternative splicing of a subset of target genes, including FIP1L1, NKTR, and ADD3 by exon skipping. Elimination of full-length FIP1L1, NKTR, and ADD3 rescued the impaired cell proliferation through CDYL2a depletion. In contrast, CDYL2b localized to heterochromatin and transcriptionally repressed several metastasis-promoting genes, including HPSE, HLA-F, and SELL. Restoration of HPSE, HLA-F, or SELL expression in CDYL2b-overexpressing cells attenuated the ability of CDYL2b to suppress breast cancer cell migration and invasion. Conclusions: Collectively, these findings establish an isoform-specific function of CDYL2 in breast cancer development and progression and highlight that pharmacological inhibition of the CDYL2a, but not the CDYL2b, isoform may be an effective strategy for breast cancer therapy.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Processamento Alternativo/genética , Processamento Alternativo/fisiologia , Animais , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/genética , Movimento Celular/fisiologia , Proliferação de Células/genética , Proliferação de Células/fisiologia , Imunoprecipitação da Cromatina , Éxons/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Células MCF-7 , Camundongos , Camundongos Nus
6.
Nucleic Acids Res ; 48(7): 3638-3656, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32112098

RESUMO

MORC family CW-type zinc finger 2 (MORC2) is an oncogenic chromatin-remodeling enzyme with an emerging role in DNA repair. Here, we report a novel function for MORC2 in cell-cycle checkpoint control through an acetylation-dependent mechanism. MORC2 is acetylated by the acetyltransferase NAT10 at lysine 767 (K767Ac) and this process is counteracted by the deacetylase SIRT2 under unperturbed conditions. DNA-damaging chemotherapeutic agents and ionizing radiation stimulate MORC2 K767Ac through enhancing the interaction between MORC2 and NAT10. Notably, acetylated MORC2 binds to histone H3 phosphorylation at threonine 11 (H3T11P) and is essential for DNA damage-induced reduction of H3T11P and transcriptional repression of its downstream target genes CDK1 and Cyclin B1, thus contributing to DNA damage-induced G2 checkpoint activation. Chemical inhibition or depletion of NAT10 or expression of an acetylation-defective MORC2 (K767R) forces cells to pass through G2 checkpoint, resulting in hypersensitivity to DNA-damaging agents. Moreover, MORC2 acetylation levels are associated with elevated NAT10 expression in clinical breast tumor samples. Together, these findings uncover a previously unrecognized role for MORC2 in regulating DNA damage-induced G2 checkpoint through NAT10-mediated acetylation and provide a potential therapeutic strategy to sensitize breast cancer cells to DNA-damaging chemotherapy and radiotherapy by targeting NAT10.


Assuntos
Neoplasias da Mama/enzimologia , Dano ao DNA , Pontos de Checagem da Fase G2 do Ciclo Celular , Acetiltransferases N-Terminal/metabolismo , Fatores de Transcrição/metabolismo , Acetilação , Antineoplásicos , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Proteína Quinase CDC2/genética , Proteína Quinase CDC2/metabolismo , Linhagem Celular Tumoral , Ciclina B1/genética , Ciclina B1/metabolismo , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Histonas/metabolismo , Humanos , Lisina/metabolismo , Radiação Ionizante , Sirtuína 2/metabolismo , Fatores de Transcrição/química
7.
Am J Surg ; 220(4): 945-951, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32145919

RESUMO

BACKGROUND: The role of surgery in breast cancer liver metastases (BCLM) remains elusive, and current application is limited. Our aim is to investigate whether hepatic resection (HR) of BCLM improves survival compared with non-hepatic resection (NHR) treatment. METHODS: Three hundred and eighty-four patients with BCLM from 2008 to 2018 were divided into two groups. Propensity score matching (PSM) analysis was used to compare the clinical outcomes. RESULTS: After PSM the mean overall survival (OS) and the 1, 3, and 5-year OS rates in HR group were 61.8 months, 92.6%, 54.7% and 54.7%, respectively; while for NHR group these values were 38.6 months, 79.2%, 45.6% and 21.9%, respectively (p < 0.007). Multivariate analysis indicated hormonal receptor status (p = 0.039) and hepatic resection (p = 0.032) were independent prognostic factors. CONCLUSION: Our study revealed that hepatectomy yields a survival benefit safely compared with medical treatments, especially for patients with positive hormonal receptors.


Assuntos
Neoplasias da Mama/terapia , Hepatectomia/métodos , Neoplasias Hepáticas/terapia , Pontuação de Propensão , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/mortalidade , China/epidemiologia , Terapia Combinada/métodos , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Pessoa de Meia-Idade , Taxa de Sobrevida/tendências , Resultado do Tratamento
8.
Breast Cancer Res Treat ; 180(2): 423-428, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32034581

RESUMO

OBJECTIVE: The aim of the study is to evaluate the optimal timing of sentinel lymph node biopsy (SLNB) in patients with clinical negative axillary lymph nodes (ALNs) before neoadjuvant therapy (NAT) and the feasibility of SLNB substituting for ALN dissection in patients with positive ALNs who convert to node negative, for HER2-positive disease. METHODS: Patients receiving SLNB with dual tracer mapping in the PEONY trial were analyzed. RESULTS: For 80 patients with clinical negative ALNs, the node negative rate by pathology after NAT was 83.8%. SLNB was performed after NAT in 71 patients. The identification rate of sentinel lymph nodes (SLNs) was 100%. For patients with positive ALNs before NAT, the axillary pathologic complete response rate in the dual HER2 blockade arm was significantly higher than that in the single blockade arm (p = 0.002). SLNB was performed in 71 patients. The identification rate was 100% and the false-negative rate was 17.2%. The false-negative rates were 33.3%, 14.3%, and 0 when 1, 2, and more than 2 SLNs were detected. There was no false-negative case when more than 1 SLN and the clipped nodes were removed simultaneously. CONCLUSIONS: For clinical ALN negative patients, HER2-positive subtype is found to have high node negative rate by pathology and it is recommended to undergo SLNB after NAT. For patients with positive ALNs who convert to negative, the false-negative rate is high. Dual tracer mapping, more than 2 SLNs detected, more than 1 SLN identified plus the clips placed are the guarantees for lower false-negative rate.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Terapia Neoadjuvante/métodos , Receptor ErbB-2/metabolismo , Biópsia de Linfonodo Sentinela/métodos , Adulto , Idoso , Axila , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Método Duplo-Cego , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Resultado do Tratamento , Adulto Jovem
9.
Cell Death Differ ; 27(3): 1105-1118, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31406303

RESUMO

Deregulation of E3 ubiquitin ligases is intimately implicated in breast cancer pathogenesis and progression, but the underlying mechanisms still remain elusive. Here we report that RING finger protein 144A (RNF144A), a poorly characterized member of the RING-in-between-RING family of E3 ubiquitin ligases, functions as a tumor suppressor in breast cancer. RNF144A was  downregulated in a subset of primary breast tumors and restoration of RNF144A suppressed breast cancer cell proliferation, colony formation, migration, invasion in vitro, tumor growth, and lung metastasis in vivo. In contrast, knockdown of RNF144A promoted malignant phenotypes of breast cancer cells. Quantitative proteomics and biochemical analysis revealed that RNF144A interacted with and targeted heat-shock protein family A member 2 (HSPA2), a putative oncoprotein that is frequently upregulated in human cancer and promotes tumor growth and progression, for ubiquitination and degradation. Notably, the ligase activity-defective mutants of RNF144A impaired its ability to induce ubiquitination and degradation of HSPA2, and to suppress breast cancer cell proliferation, migration, and invasion as compared with its wild-type counterpart. Moreover, RNF144A-mediated suppression of breast cancer cell proliferation, migration, and invasion was rescued by ectopic HSPA2 expression. Clinically, low RNF144A and high HSPA2 expression in breast cancer patients was correlated with aggressive clinicopathological characteristics and decreased overall and disease-free survival. Collectively, these findings reveal a previously unappreciated role for RNF144A in suppression of breast cancer growth and metastasis, and identify RNF144A as the first, to our knowledge, E3 ubiquitin ligase for HSPA2 in human cancer.


Assuntos
Neoplasias da Mama/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Oncogenes , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação para Baixo/genética , Feminino , Humanos , Neoplasias Pulmonares/secundário , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Biológicos , Invasividade Neoplásica , Prognóstico , Complexo de Endopeptidases do Proteassoma/metabolismo , Estabilidade Proteica , Proteólise , Ubiquitinação , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Breast Cancer Res Treat ; 178(2): 251-261, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31388936

RESUMO

PURPOSE: Limited knowledge exists on the detection of breast cancer stem cell (BCSC)-related mutations in circulating free DNA (cfDNA) from patients with advanced cancers. Identification of new cancer biomarkers may allow for earlier detection of disease progression and treatment strategy modifications. METHODS: We conducted a prospective study to determine the feasibility and prognostic utility of droplet digital polymerase chain reaction (ddPCR)-based BCSC gene mutation analysis of cfDNA in patients with breast cancer. RESULTS: Detection of quantitative BCSC gene mutation in cfDNA by ddPCR mirrors disease progression and thus may represent a valuable and cost-effective measure of tumor burden. We have previously shown that hematological and neurological expressed 1-like (HN1L), ribosomal protein L39 (RPL39), and myeloid leukemia factor 2 (MLF2) are novel targets for BCSC self-renewal, and targeting these genetic alterations could be useful for personalized genomic-based therapy. CONCLUSION: BCSC mutation detection in cfDNA may have important implications for diagnosis, prognosis, and serial monitoring.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Transformação Celular Neoplásica/genética , DNA Tumoral Circulante , Mutação , Células-Tronco Neoplásicas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/sangue , Neoplasias da Mama/mortalidade , Análise Mutacional de DNA , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico
11.
Quant Imaging Med Surg ; 9(3): 418-426, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31032189

RESUMO

Background: The visualization of microvasculature is an essential step in understanding the mechanisms underlying early vessel disorders involved in breast cancer and for developing effective therapeutic strategies. However, generating detailed and reproducible data using immunohistochemistry analysis of breast cancer angiogenesis has been difficult. Methods: To analyze the diversification of angiogenesis in the development of tumor growth and evaluate the anti-vascular effects of Avastin (bevacizumab), we used new X-ray microangiography and third-generation synchrotron radiation-based micro-computed tomography (SR micro-CT) technology. With these techniques, we were able to investigate the structures and density of microvessels in xenograft mouse models (n=24). Barium sulfate nanoparticles were injected into the left cardiac ventricle of the mice to allow the visualization of blood vessels. Results: Three-dimensional structures of microvessels were displayed with a high spatial image resolution of 20-30 µm. The density of angiogenesis and the incidence of lung metastasis were significantly reduced in xenograft mouse models of breast cancer treated with Avastin compared with control groups. Also, the density of smaller vessels (diameter <50 µm) was significantly decreased in the Avastin-treated mice, while the density of larger vessels (diameter >100 µm) was not significantly changed. Conclusions: Avastin inhibited tumor growth and lung metastasis by reducing microvessels. Additionally, synchrotron radiation (SR) techniques are useful as an additional tool for more precise quantification of angiogenesis.

12.
Int J Clin Oncol ; 24(8): 934-940, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30888527

RESUMO

BACKGROUND: With the improvement in the survival of breast cancer, developing second primary malignancy becomes a serious health issue. The aim of this study was to explore the survival of breast cancer patients with second primary malignancy, and to evaluate the impact of chemotherapy on the risk of different cancer sites. METHOD: Obtaining data from the Surveillance, Epidemiology, and End Results database, we calculated the standardized incidence ratio (SIR) for second primary malignancy in breast cancer survivors between 2000 and 2014. Overall survival and cancer-specific survival were analyzed with Kaplan-Meier method. Then, we further conducted stratified sub-analyses according to chemotherapy. RESULTS: The overall risk of second primary cancer for all sites was significantly elevated in breast cancer patients (SIR = 1.15, 95% CI 1.14-1.16). Overall survival and cancer-specific survival of the patients with breast cancer only were significantly better than the patients with multiple primary cancers (both P < 0.001). Chemotherapy was associated with increased incidences for all sites, except lymphoma, myeloma, and chronic lymphocytic leukemia (SIR = 0.80, 95% CI 0.72-0.88; SIR = 0.85, 95% CI 0.71-1.01; SIR = 0.57, 95% CI 0.43-0.74, respectively). The risk for developing second acute myeloid leukemia after chemotherapy in breast cancer patients varied with age and latency. CONCLUSION: Female breast cancer patients showed higher incidence of second primary malignancy, which was associated with poorer prognosis. Chemotherapy benefits should be weighed against the risks of second primary malignancy.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias da Mama/mortalidade , Segunda Neoplasia Primária/induzido quimicamente , Programa de SEER , Adulto , Idoso , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Segunda Neoplasia Primária/patologia , Estudos Retrospectivos , Risco , Fatores de Risco , Taxa de Sobrevida , Adulto Jovem
13.
Cancer Med ; 7(12): 6393-6400, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30480382

RESUMO

BACKGROUND: Thyroid cancer (TC) is one of the most commonly seen secondary malignancy in breast cancer (BC) survivors. MATERIALS AND METHODS: A retrospective study was conducted in BC patients in our center from 1999 to 2013. Patients were divided into BC-TC group and BC-alone group. RESULTS: In total, 13 978 BC patients were identified, among whom 247 (1.8%) had TC. The standardized incidence ratio (SIR) of TC was 4.48 compared with Chinese females, and up to 98.0% of cases were thyroid papillary carcinomas. A family history of malignancy was the only independent risk factor (odds ratio = 1.457, P = 0.025) for development of TC in patients with BC. We also identified inferior survival in patients with synchronous versus metachronous BC-TC (P = 0.016). Synchronous BC-TC (risk ratio = 5.597, P = 0.018) was an independent prognostic factor for inferior RFS. CONCLUSIONS: We observed high co-occurrence of TC in patients with BC. There might be different mechanisms behind synchronous and metachronous BC-TC.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias Primárias Múltiplas/epidemiologia , Neoplasias da Glândula Tireoide/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
14.
Cancer Res ; 78(18): 5274-5286, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-29945959

RESUMO

The molecular underpinnings behind malignant progression of breast cancer from a localized lesion to an invasive and ultimately metastatic disease are incompletely understood. Here, we report that F-box only protein 22 (FBXO22) plays a dual role in mammary tumorigenesis and metastasis. FBXO22 was upregulated in primary breast tumors and promoted cell proliferation and colony formation in vitro and xenograft tumorigenicity in vivo Surprisingly, FBXO22 suppressed epithelial-mesenchymal transition (EMT), cell motility, and invasiveness in vitro and metastatic lung colonization in vivo Clinical data showed that expression levels of FBXO22 were associated with favorable clinical outcomes, supporting the notion that metastasis, rather than primary cancer, is the major determinant of the mortality of patients with breast cancer. Mechanistic investigations further revealed that FBXO22 elicits its antimetastatic effects by targeting SNAIL, a master regulator of EMT and breast cancer metastasis, for ubiquitin-mediated proteasomal degradation in a glycogen synthase kinase 3ß phosphorylation-dependent manner. Importantly, expression of SNAIL rescued FBXO22-mediated suppression of EMT, cell migration, and invasion. A patient-derived tryptophan-to-arginine mutation at residue 52 (W52R) within the F-box domain impaired FBXO22 binding to the SKP1-Cullin1 complex and blocked FBXO22-mediated SNAIL degradation, thus abrogating the ability of FBXO22 to suppress cell migration, invasion, and metastasis. Collectively, these findings uncover an unexpected dual role for FBXO22 in mammary tumorigenesis and metastatic progression and delineate the mechanism of an oncogenic mutation of FBXO22 in breast cancer progression.Significance: These findings highlight the paradoxical roles of FBXO22 in breast cancer, as it promotes breast tumor cell proliferation but prevents EMT and metastasis. Cancer Res; 78(18); 5274-86. ©2018 AACR.


Assuntos
Neoplasias da Mama/patologia , Carcinogênese , Proteínas F-Box/fisiologia , Metástase Neoplásica , Receptores Citoplasmáticos e Nucleares/fisiologia , Motivos de Aminoácidos , Animais , Neoplasias da Mama/metabolismo , Movimento Celular , Proliferação de Células , Progressão da Doença , Transição Epitelial-Mesenquimal , Feminino , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Transplante de Neoplasias , Fosforilação , Resultado do Tratamento
15.
Cancer Res ; 78(11): 3087-3097, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29572226

RESUMO

Genome-wide association studies have identified more than 90 susceptibility loci for breast cancer. However, the missing heritability is evident, and the contributions of coding variants to breast cancer susceptibility have not yet been systematically evaluated. Here, we present a large-scale whole-exome association study for breast cancer consisting of 24,162 individuals (10,055 cases and 14,107 controls). In addition to replicating known susceptibility loci (e.g., ESR1, FGFR2, and TOX3), we identify two novel missense variants in C21orf58 (rs13047478, Pmeta = 4.52 × 10-8) and ZNF526 (rs3810151, Pmeta = 7.60 × 10-9) and one new noncoding variant at 7q21.11 (P < 5 × 10-8). C21orf58 and ZNF526 possessed functional roles in the control of breast cancer cell growth, and the two coding variants were found to be the eQTL for several nearby genes. rs13047478 was significantly (P < 5.00 × 10-8) associated with the expression of genes MCM3AP and YBEY in breast mammary tissues. rs3810151 was found to be significantly associated with the expression of genes PAFAH1B3 (P = 8.39 × 10-8) and CNFN (P = 3.77 × 10-4) in human blood samples. C21orf58 and ZNF526, together with these eQTL genes, were differentially expressed in breast tumors versus normal breast. Our study reveals additional loci and novel genes for genetic predisposition to breast cancer and highlights a polygenic basis of disease development.Significance: Large-scale genetic screening identifies novel missense variants and a noncoding variant as predisposing factors for breast cancer. Cancer Res; 78(11); 3087-97. ©2018 AACR.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Neoplasias da Mama/genética , Exoma/genética , Predisposição Genética para Doença/genética , Locos de Características Quantitativas/genética , Adulto , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética
16.
Cancer Med ; 7(4): 1317-1325, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29473320

RESUMO

Emerging evidence shows that ring finger protein 144A (RNF144A), a poorly characterized member of the Ring-between-Ring (RBR) family of E3 ubiquitin ligases, is a potential tumor suppressor gene. However, its regulatory mechanism in breast cancer remains undefined. Here, we report that RNF144A promoter contains a putative CpG island and the methylation levels of RNF144A promoter are higher in primary breast tumors than those in normal breast tissues. Consistently, RNF144A promoter methylation levels are associated with its transcriptional silencing in breast cancer cells, and treatment with DNA methylation inhibitor 5-Aza-2-deoxycytidine (AZA) reactivates RNF144A expression in cells with RNF144A promoter hypermethylation. Furthermore, genetic knockdown or pharmacological inhibition of endogenous methyl-CpG-binding domain 4 (MBD4) results in increased RNF144A expression. These findings suggest that RNF144A is epigenetically silenced in breast cancer cells by promoter hypermethylation and MBD4.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Proteínas de Transporte/genética , Metilação de DNA , Endodesoxirribonucleases/metabolismo , Epigênese Genética , Inativação Gênica , Regiões Promotoras Genéticas , Ubiquitina-Proteína Ligases/genética , Adulto , Idoso , Sítios de Ligação , Ilhas de CpG , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Ligação Proteica
17.
Sci Rep ; 8(1): 2225, 2018 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-29396508

RESUMO

Although microRNA-301a (miR-301a) has been reported to function as an oncogene in many human cancers, there are limited data regarding miR-301a and breast tumours. In this study, we first detected the expression of miR-301a using an in situ hybridization (ISH) -based classification system in 380 samples of BC tissue, including both non-TNBC (triple-negative breast cancer) and TNBC specimens. Our results suggest that analysing miR-301a expression in breast tissue biopsy specimens at the time of diagnosis could have the potential to identify patients who might be candidates for active surveillance. We validated our results that higher expression of miR-301a is associated with a decreased OS in independent public breast cancer databases, such as TCGA and METABRIC, using the online webtool Kaplan-Meier Plotter, which provided additional powerful evidence to confirm the prognostic value of miR-301a. MiR-301a may serve as a potential therapeutic target for patients with breast cancer. According to our results, miR-301a should be considered, and novel therapeutic options are needed to target this aggressive miR-301a-positive type of breast cancer to reduce recurrence and the mortality rate.


Assuntos
MicroRNAs/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidade , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Biópsia , Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Hibridização In Situ , Estimativa de Kaplan-Meier , MicroRNAs/biossíntese , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Prognóstico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
18.
Oncotarget ; 8(58): 97941-97954, 2017 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-29228664

RESUMO

MORC family CW-type zinc finger 2 (MORC2) is a newly identified chromatin remodeling protein with emerging roles in the regulation of DNA damage response and gene transcription, but its mechanistic role in breast cancer development and progression remains unexplored. Here, we show that MORC2 promoted breast cancer invasion and metastasis and these effects depended on a proline-rich domain (PRD) within its carboxy-terminal region spanning residues 601-734. Induced expression of wild-type MORC2 did not significantly affect cell proliferation and cell-cycle progression, but promoted breast cancer cell migration and invasion in vitro and metastatic lung colonization in vivo. The PRD domain was dispensable for the protein stability and subcellular localization of MORC2, but depletion of the PRD domain substantially suppressed MORC2-mediated migration, invasion, and metastasis. Proteomic and biochemical analyses further demonstrated that wild-type MORC2, but not PRD deletion mutant, interacted with catenin delta 1 (CTNND1), a cadherin-associated protein that participates in tumor invasion and metastasis. Moreover, knockdown of endogenous CTNND1 by short hairpin RNAs suppressed the migratory and invasive potential of MORC2-expressing cells. Taken together, these results suggest that MORC2 promotes breast cancer invasion and metastasis through its PRD domain-mediated interaction with CTNND1.

19.
Oncotarget ; 8(55): 94505-94518, 2017 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-29212245

RESUMO

Poly(ADP-ribose) polymerase 1 (PARP1), a critical DNA repair protein, is frequently upregulated in breast tumors with a key role in breast cancer progression. Consequently, PARP inhibitors have emerged as promising therapeutics for breast cancers with DNA repair deficiencies. However, relatively little is known about the regulatory mechanism of PARP1 expression and the determinants of PARP inhibitor sensitivity in breast cancer cells. Here, we report that ring finger protein 144A (RNF144A), a RING-between-RING (RBR)-type E3 ubiquitin ligase with an unexplored functional role in human cancers, interacts with PARP1 through its carboxy-terminal region containing the transmembrane domain, and targets PARP1 for ubiquitination and subsequent proteasomal degradation. Moreover, induced expression of RNF144A decreases PARP1 protein levels and renders breast cancer cells resistant to the clinical-grade PARP inhibitor olaparib. Conversely, knockdown of endogenous RNF144A increases PARP1 protein levels and enhances cellular sensitivity to olaparib. Together, these findings define RNF144A as a novel regulator of PARP1 protein abundance and a potential determinant of PARP inhibitor sensitivity in breast cancer cells, which may eventually guide the optimal use of PARP inhibitors in the clinic.

20.
Biochem Biophys Res Commun ; 493(3): 1159-1167, 2017 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-28943434

RESUMO

BACKGROUND: Chemokine (C-X-C motif) ligand 17 (CXCL17) is the latest member of the chemokine family. However, its function in various cancer types is unknown. The G protein-coupled receptor 35 (GPR35) was identified as the receptor of CXCL17 and named recently as CXCR8. The function of the CXCL17-CXCR8 (GPR35) biological axis in cancer has not been reported. METHODS: The expression of CXCL17 and CXCR8 (GPR35) in breast cancer cell lines and a tissue microarray (TMA) was detected through western blot and immunohistochemistry (IHC). Expression data in IHC were analyzed using clinicopatholigical and survival information. RESULTS: CXCL17 and CXCR8 (GPR35) were found to be variably expressed in breast cancer cell lines. Both expressed higher in breast cancer tissue than normal adjacent tissue. Although CXCL17 can interact with CXCR8 (GPR35) in breast cancer cells in vitro, the expression correlation between these two markers in breast cancer tissue was not found to be significant. As to clinical significance, CXCR8 (GPR35) expression was found to be significantly associated with advanced histological grade and higher proliferation rate indicated by Ki-67 expression. Although CXCL17 was not found to statistically correlate with any clinicopathological characteristics, it was found to be associated with shorter overall survival and is an independent marker of poor prognosis in breast cancer. In addition, CXCL17 was found to promote proliferation and migration of breast cancer cells in vitro and in vivo. CONCLUSIONS: We investigated the role of the CXCL17-CXCR8 (GPR35) axis in breast cancer for the first time. CXCL17 is a potential oncogene and promising therapeutic target, is an independent biomarker of poor prognosis in patients with breast cancer, and can promote proliferation and migration of breast cancer cells in vitro and in vivo.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Quimiocinas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/mortalidade , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Quimiocinas/genética , Quimiocinas CXC , Feminino , Humanos , Estimativa de Kaplan-Meier , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Prognóstico , Ensaios Antitumorais Modelo de Xenoenxerto
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...