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1.
Int J Mol Sci ; 22(13)2021 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-34199096

RESUMO

Integrins participate in the pathogenesis and progression of tumors at many stages during the metastatic cascade. However, current evidence for the role of integrins in breast cancer progression is contradictory and seems to be dependent on tumor stage, differentiation status, and microenvironmental influences. While some studies suggest that loss of α2ß1 enhances cancer metastasis, other studies suggest that this integrin is pro-tumorigenic. However, few studies have looked at α2ß1 in the context of bone metastasis. In this study, we aimed to understand the role of α2ß1 integrin in breast cancer metastasis to bone. To address this, we utilized in vivo models of breast cancer metastasis to bone using MDA-MB-231 cells transfected with an α2 expression plasmid (MDA-OEα2). MDA cells overexpressing the α2 integrin subunit had increased primary tumor growth and dissemination to bone but had no change in tumor establishment and bone destruction. Further in vitro analysis revealed that tumors in the bone have decreased α2ß1 expression and increased osteolytic signaling compared to primary tumors. Taken together, these data suggest an inverse correlation between α2ß1 expression and bone-metastatic potential. Inhibiting α2ß1 expression may be beneficial to limit the expansion of primary tumors but could be harmful once tumors have established in bone.


Assuntos
Neoplasias Ósseas/secundário , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Expressão Gênica , Integrina alfa2beta1/genética , Animais , Neoplasias Ósseas/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Invasividade Neoplásica , Osteólise/genética , Osteólise/metabolismo , Fenótipo
2.
Artigo em Inglês | MEDLINE | ID: mdl-34199253

RESUMO

BACKGROUND: Breast cancer is the most common cancer among women. The Korean Genome and Epidemiology Study (KoGES) is a large cohort study that is available to the public. Using this large cohort study, we aimed to unravel the relationship between breast cancer development and a family history of breast cancer in Korea. METHODS: This cohort study relied on data from the KoGES from 2001 through 2013. A total of 211,725 participants were screened. Of these, 129,374 women were evaluated. They were divided into two groups, including participants with and without breast cancer. A logistic regression model was used to retrospectively analyze the odds ratio of breast cancer history in families of women with and without breast cancer. RESULTS: Of 129,374 women, 981 had breast cancer. The breast cancer group had more mothers and siblings with histories of breast cancer (p < 0.001). A history of breast cancer in the participant's mother resulted in an odds ratio of 3.12 (1.75-5.59), and a history of breast cancer in the participant's sibling resulted in an odds ratio of 2.63 (1.85-3.74). There was no interaction between the history of maternal breast cancer and the history of sibling breast cancer. Based on the subgroup analysis, family history was a stronger factor in premenopausal women than in menopausal and postmenopausal women. CONCLUSIONS: A family history of breast cancer is a significant risk factor for breast cancer in Korea. Premenopausal women with a maternal history of breast cancer are of particular concern. Intensive screening and risk-reducing strategies should be considered for this vulnerable subpopulation.


Assuntos
Neoplasias da Mama , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Estudos de Coortes , Feminino , Humanos , Pré-Menopausa , República da Coreia/epidemiologia , Estudos Retrospectivos , Fatores de Risco
3.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202777

RESUMO

Long noncoding RNAs (lncRNAs) have been identified as contributors to the development and progression of cancer through various functions and mechanisms. LncRNA GAS5 is downregulated in multiple cancers and acts as a tumor suppressor in breast cancer. GAS5 interacts with various proteins (e.g., E2F1, EZH2, and YAP), DNA (e.g., the insulin receptor promoter), and various microRNAs (miRNAs). In breast cancer, GAS5 binds with miR-21, miR-222, miR-221-3p, miR-196a-5p, and miR-378a-5p that indicates the presence of several elements for miRNA binding (MREs) in GAS5. Mediated by the listed miRNAs, GAS5 is involved in the upregulation of a number of mRNAs of suppressor proteins such as PTEN, PDCD4, DKK2, FOXO1, and SUFU. Furthermore, the aberrant promoter methylation is involved in the regulation of GAS5 gene expression in triple-negative breast cancer and some other carcinomas. GAS5 can stimulate apoptosis in breast cancer via diverse pathways, including cell death receptors and mitochondrial signaling pathways. GAS5 is also a key player in the regulation of some crucial signal pathways in breast cancer, such as PI3K/AKT/mTOR, Wnt/ß-catenin, and NF-κB signaling. Through epigenetic and other mechanisms, GAS5 can increase sensitivity to multiple drugs and improve prognosis. GAS5 is thus a promising target in the treatment of breast cancer patients.


Assuntos
Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , RNA Longo não Codificante/genética , Animais , Apoptose/genética , Biomarcadores Tumorais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Metilação de DNA , Epigênese Genética , Feminino , Humanos , MicroRNAs/genética , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Transdução de Sinais
4.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199510

RESUMO

During aggressive cancer progression, cancer cells adapt to unique microenvironments by withstanding various cellular stresses, including endoplasmic reticulum (ER) stress. However, the mechanism whereby cancer cells overcome the ER stress to survive remains to be elucidated. Herein, we demonstrated that microtubule acetylation in cancer cells grown on a stiff matrix promotes cancer progression by preventing excessive ER stress. Downregulation of microtubule acetylation using shRNA or CRSIPR/Cas9 techniques targeting ATAT1, which encodes α-tubulin N-acetyltransferase (αTAT1), resulted in the upregulation of ER stress markers, changes in ER morphology, and enhanced tunicamycin-induced UPR signaling in cancer cells. A set of genes involved in cancer progression, especially focal adhesion genes, were downregulated in both ATAT1-knockout and tunicamycin-treated cells, whereas ATAT1 overexpression restored the gene expression inhibited by tunicamycin. Finally, the expression of ATAT1 and ER stress marker genes were negatively correlated in various breast cancer types. Taken together, our results suggest that disruption of microtubule acetylation is a potent therapeutic tool for preventing breast cancer progression through the upregulation of ER stress. Moreover, ATAT1 and ER stress marker genes may be useful diagnostic markers in various breast cancer types.


Assuntos
Acetiltransferases/genética , Neoplasias da Mama/genética , Estresse do Retículo Endoplasmático/genética , Proteínas dos Microtúbulos/genética , Tunicamicina/farmacologia , Acetilação/efeitos dos fármacos , Acetiltransferases/antagonistas & inibidores , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas dos Microtúbulos/antagonistas & inibidores , Microtúbulos/efeitos dos fármacos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Microambiente Tumoral/efeitos dos fármacos
5.
Int J Mol Sci ; 22(11)2021 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-34204158

RESUMO

Breast cancer (BC) is the most predominant type of cancer among women. The aim of this study is to find new biomarkers that can help in early detection of BC, especially for those who are too young to be screened using mammography as per guidelines. Using microRNA microarray, we previously showed dysregulation of 74 microRNAs in tumors from early BC patients as compared with normal adjacent tissues, which we were interested in studying in blood circulation. In this study, we investigated the expression of 12 microRNA (miR-21/miR-155/miR-23a/miR-130a/miR-145/miR-425-5p/miR-139-5p/miR-451/miR-195/miR-125b/miR-100, and miR-182) in the plasma of 41 newly diagnosed Lebanese BC patients with early invasive ductal carcinoma as compared with 32 healthy controls. Total RNA was extracted from plasma, and expression levels of miRNA of interest were measured using RT-qPCR followed by statistical analysis; miR-21, miR-155, miR-23a, miR-130a, miR-145, miR-425-5p, and miR-139-5p were significantly upregulated and miR-451 was significantly downregulated, in the plasma of BC patients as compared with healthy controls. The positively correlated miR-23a, miR-21, and miR-130a had a high diagnostic accuracy (86%). Importantly, the combination of miR-145/miR-425-5p/miR-139-5p/miR-130a scored the highest diagnostic accuracy of 95% with AUC = 0.97 (sensitivity 97% and specificity 91%). MicroRNAs are promising non-invasive diagnostic biomarkers for early-stage BC with the panel of miR-145/miR-425-5p/miR-139-5p/miR-130a having the highest diagnostic accuracy.


Assuntos
Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Neoplasias da Mama/sangue , Neoplasias da Mama/diagnóstico , MicroRNA Circulante/sangue , MicroRNA Circulante/genética , Perfilação da Expressão Gênica , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estatísticas não Paramétricas , Adulto Jovem
6.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205118

RESUMO

During metastasis, cancer cells that originate from the primary tumor circulate in the bloodstream, extravasate, and form micrometastases at distant locations. Several lines of evidence suggest that specific interactions between cancer cells and endothelial cells, in particular tumor cell adhesion to the endothelium and transendothelial migration, play a crucial role in extravasation. Here we have studied the role of vascular endothelial (VE)-cadherin which is expressed aberrantly by breast cancer cells and might promote such interactions. By comparing different human breast cancer cell lines, we observed that the number of cancer cells that adhered to endothelium correlated with VE-cadherin expression levels. VE-cadherin silencing experiments confirmed that VE-cadherin enhances cancer cell adhesion to endothelial cells. However, in contrast, the number of cancer cells that incorporated into the endothelium was not dependent on VE-cadherin. Thus, it appears that cancer cell adhesion and incorporation are distinct processes that are governed by different molecular mechanisms. When cancer cells incorporated into the endothelial monolayer, they formed VE-cadherin positive contacts with endothelial cells. On the other hand, we also observed tumor cells that had displaced endothelial cells, reflecting either different modes of incorporation, or a temporal sequence where cancer cells first form contact with endothelial cells and then displace them to facilitate transmigration. Taken together, these results show that VE-cadherin promotes the adhesion of breast cancer cells to the endothelium and is involved in the initial phase of incorporation, but not their transmigration. Thus, VE-cadherin might be of relevance for therapeutic strategies aiming at preventing the metastatic spread of breast cancer cells.


Assuntos
Antígenos CD/genética , Neoplasias da Mama/genética , Caderinas/genética , Adesão Celular/genética , Endotélio Vascular/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Técnicas de Cocultura , Endotélio Vascular/patologia , Endotélio Vascular/ultraestrutura , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Células Endoteliais da Veia Umbilical Humana/citologia , Humanos , Imagem Molecular/métodos , Metástase Neoplásica
8.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 37(8): 722-727, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34236032

RESUMO

Objective To investigate the effect of knocking down hexokinase 2 (HK2) on the proliferation and drug resistance of breast cancer cells and its mechanism. Methods The MDA-MB-231 breast cancer cells were transfected with the short hairpin RNA (shRNA) plasmid. The mRNA and protein levels of HK2 were detected by real-time quantitative PCR and Western blotting, respectively; MTT assay was used to detect the effect of HK2 on the proliferation and 5-fluorouraci (5-FU) resistance of breast cancer cells; Lactate assay and extracellular acidification rate (ECAR) were used to detect the effect of HK2 on the glycolysis of breast cancer cells. Results The breast cancer cell line with stable & low expression of HK2 was obtained, and the mRNA and protein levels of HK2 were significantly reduced. Knockdown of HK2 significantly inhibited the proliferation of breast cancer cells and enhanced the killing effect of 5-FU on them. Down regulation of HK2 significantly inhibited the lactate secretion and lowered the glycolysis baseline in breast cancer cells. Conclusion Knockdown of HK2 inhibits the proliferation of MDA-MB-231 breast cancer cells and reduce their resistance to 5-FU.


Assuntos
Neoplasias da Mama , Hexoquinase , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Fluoruracila/farmacologia , Glicólise , Hexoquinase/genética , Hexoquinase/metabolismo , Humanos
9.
Anticancer Res ; 41(7): 3409-3417, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230136

RESUMO

BACKGROUND/AIM: ER-positive breast cancer patients commonly undergo endocrine therapy with drugs such as tamoxifen. Despite tamoxifen being a highly effective drug, long-term treatment results in resistance in one-third of the patients. Although many explanations for the development of tamoxifen resistance have been put forward, a clearly defined underlying mechanism is still lacking. MATERIALS AND METHODS: The expression level of HOXB5 was evaluated between MCF7 breast cancer cells and tamoxifen-resistant MCF7 (TAMR) cells by RT-PCR. Then, the effect of HOXB5 on invasion and migration abilities as well as on cancer stemness were investigated through 3D culture and spheroid formation assay. RESULTS: In this study, we provide evidence that HOXB5 is up-regulated in TAMR cells. EGFR is concurrently overexpressed, and the EGFR signaling cascade is activated, resulting in migratory and invasive phenotypes in TAMR cells compared to MCF7 cells. However, HOXB5 knockdown in TAMR cells resulted in the de-activation of the EGFR signaling pathway, less aggressive phenotypes and restoration of sensitivity to tamoxifen treatment. More interestingly, TAMR cells expressed higher levels of stem cell markers, and as a result, their enhanced stemness allowed for a better formation of spheroids than MCF7 cells. When HOXB5 was overexpressed in MCF7 cells, they were able to form a larger number of spheroids as in TAMR cells. CONCLUSION: HOXB5 is one of the key factors involved in tumor aggression and progression in tamoxifen-resistant breast cancer cells.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Movimento Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Homeodomínio/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Progressão da Doença , Receptores ErbB/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Células MCF-7 , Transdução de Sinais/genética , Células-Tronco/patologia , Tamoxifeno/farmacologia
10.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(6): 854-861, 2021 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-34238737

RESUMO

OBJECTIVE: To detect the expression of miR-4719 in breast cancer tissues and cells and explore its role in regulating invasion and migration of breast cancer cells. OBJECTIVE: qRT-PCR was used to detect the expression of miR-4719 and ARHGAP36 in 30 pairs of human breast cancer tissues and adjacent tissues, two breast cancer cell lines (BT549 and MDA-MB- 231) and normal breast cells (MCF-10A). Bioinformatic methods were utilized to analyze the relationship between miR-4719 expression and overall survival of breast cancer patients and predict the potential target gene miR- 4719. miR-4719 mimics, ARHGAP36 shRNA and ARHGAP36 plasmids were transfected into breast cancer cells to test the effects of miR-4719 overexpression, ARHGAP36 knockdown and ARHGAP36 overexpression on cell migration and invasion using wound healing assay and Transwell assay. A dual-luciferase reporter assay was used to verify the direct binding between miR-4719 and 3'-UTR of ARHGAP36. OBJECTIVE: Compared with those in adjacent tissues or normal breast cells, the expressions of miR-4719 were significantly decreased and the expression of ARHGAP36 was increased in breast cancer tissues (P < 0.001) and breast cancer cell lines (P < 0.01). A low expression of miR-4719 was correlated with a poorer overall survival of breast cancer patients (P < 0.05). Overexpression of miR-4719 and ARHGAP36 knockdown both significantly attenuated the invasion and migration abilities of breast cancer cells (P < 0.05). The expression of miR-4719 was inversely correlated to that of ARHGAP36 in breast cancer tissues (P < 0.01). Dual-luciferase reporter assay confirmed that ARHGAP36 was the target gene of miR-4719 (P < 0.01), and exogenous miR-4719 could significantly lower the expression of ARHGAP36 (P < 0.05). ARHGAP36 overexpression significantly reversed the inhibitory effects of miR-4719 mimics on migration and invasion of breast cancer cells (P < 0.05). OBJECTIVE: The expression of miR-4719 is aberrantly decreased in breast cancer tissues to promote migration and invasion of breast cancer cells by up-regulating ARHGAP36 expression.


Assuntos
Neoplasias da Mama , MicroRNAs , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Invasividade Neoplásica/genética
11.
J Coll Physicians Surg Pak ; 30(7): 837-840, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34271787

RESUMO

OBJECTIVE: To test the germline oncogenic mutations in BRCA1 and BRCA2 genes, associated with triple-negative breast cancer (TNBC) patients under study, by targeted sequencing of their DNA with next-generation sequencing (NGS) platform. STUDY DESIGN: Cross-sectional observational study. PLACE AND DURATION OF STUDY: Histopathology Department, Armed Forces Institute of Pathology (AFIP) Rawalpindi, Pakistan from May to June 2020. METHODOLOGY: Peripheral blood of 14 women (aged ≤60) with triple negative breast carcinoma (TNBC) was taken with the consent of performing germline genetic testing. Targeted NGS was performed for all coding regions and splicing sites of BRCA1 and BRCA2 genes, using AmpliSeq for Illumina BRCA Panel and Illumina MiSeq sequencer (placed at AFIP). Analysis and interpretation of the sequencing results have been done by using Illumina bioinformatics tools and external databases. RESULTS: Two hundred and fifty-four variants were detected in BRCA1 and BRCA2 genes, having variant quality score of 100 in all cases under study. As a result, two pathogenic variants and three variants of uncertain significance were interpreted in this germline pipeline. Cases with pathogenic variants had early onset breast cancer with age less than 35. CONCLUSION: Germline variants in BRCA were detected in the known cases of TNBC, which will not only identify the most prevalent mutations in this region; but will also make them a candidate to receive targeted therapies, which was previously not possible without genetic testing. Moreover, this study further validates the importance of early BRCA genetic screening in young patients, who have positive family history of breast carcinoma. Key Words: Breast cancer, Triple negative, Next-generation sequencing, BRCA1, BRCA2.


Assuntos
Neoplasias da Mama , Neoplasias da Mama/genética , Estudos Transversais , Feminino , Predisposição Genética para Doença , Testes Genéticos , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Paquistão
12.
Gene ; 796-797: 145805, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34197949

RESUMO

Breast Cancer Stem Cells has become the toast of many breast cancer investigators in the past two decades owing to their crucial roles in tumourigenesis, progression, differentiation, survival and chemoresistance. Despite the growing list of research data in this field, racial or ethnic comparison studies on these stem cells remain scanty. This study is a comparative racial analysis of putative breast cancer stem cells. Research articles on the clinicopathological significance of breast cancer stem cells within a period of 17 years (2003-2020) were reviewed across 5 major races (African/Black American, Asian, Caucasian/White, Hispanic/Latino, and American). The associations between the stem cells markers (CD44+/CD24-/low, BMI1, ALDH1, CD133, and GD2) and clinicopathological and clinical outcomes were analysed. A total of 40 studies were included in this study with 50% Asian, 25% Caucasian, 10% African, 5% American and 2.5% Hispanic/Latino, and 7.5% other mixed races. CD44+/CD24-/low has been associated with TNBC/Basal like phenotype across all races. It is generally associated with poor clinicopathological features such as age, tumour size, lymph node metastasis and lymphovascular invasion. In Asians, CD44+/CD24-/low was associated with DFS and OS but not in Caucasians. ALDH1 was the most studied breast CSC marker (40% of all studies on breast cancer stem cell markers) also associated with poor clinicopathological features including size, age, stage, lymph node metastasis and Nottingham Prognostic Index. ALDH1 was also associated with DFS and OS in Asians but not Caucasians. Racial variations exist in breast cancer stem cell pattern and functions but ill-defined due to multiple factors. Further research is required to better understand the role of breast CSC.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Células-Tronco Neoplásicas/metabolismo , Antígeno AC133/genética , Família Aldeído Desidrogenase 1/genética , Antígeno CD24/genética , Grupos de Populações Continentais/genética , Intervalo Livre de Doença , Feminino , Humanos , Receptores de Hialuronatos/genética , Complexo Repressor Polycomb 1/genética , Fatores Raciais
13.
Biosens Bioelectron ; 190: 113470, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34229191

RESUMO

MicroRNAs (miRNAs) are promising biomarkers for the early diagnosis of breast cancer. Yet, simultaneous achievement of rapid, sensitive and accurate detection of diverse miRNAs in clinical samples is still challenging due to the low abundance of miRNAs and the complex procedures of RNA extraction and separation. Herein, we develop an innovative three-dimensional (3D) surface-enhanced Raman scattering (SERS) holography sensing strategy for rapid, sensitive and multiplexed detection of human breast cancer-associated miRNAs. To establish a proof of concept, nine kinds of human breast cancer-associated miRNAs are isothermally amplified by Exonuclease (Exo) III enzyme, and the products could be spatially separated to corresponding sensing region on silicon SERS substrates. Each region has been modified with corresponding hairpin DNA probes, which are used to identify and quantify the miRNAs. Different DNA probes are labeled with different Raman reporters, which serve as "SERS tags" to incorporate spectroscopic information into computer-generated 3D SERS hologram within ~9 min. We demonstrate that 3D SERS holography chip not only achieves an ultrahigh sensitivity down to ~1 aM but also feature a high correlation with RT-qPCR in the detection of nine miRNAs in 30 clinical serum samples. This work provides a feasible tool to improve the diagnosis of breast cancer.


Assuntos
Técnicas Biossensoriais , Neoplasias da Mama , Holografia , Nanopartículas Metálicas , MicroRNAs , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Feminino , Humanos , MicroRNAs/genética , Análise Espectral Raman
14.
Nat Commun ; 12(1): 4198, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34234117

RESUMO

Our study describes breast cancer risk loci using a cross-ancestry GWAS approach. We first identify variants that are associated with breast cancer at P < 0.05 from African ancestry GWAS meta-analysis (9241 cases and 10193 controls), then meta-analyze with European ancestry GWAS data (122977 cases and 105974 controls) from the Breast Cancer Association Consortium. The approach identifies four loci for overall breast cancer risk [1p13.3, 5q31.1, 15q24 (two independent signals), and 15q26.3] and two loci for estrogen receptor-negative disease (1q41 and 7q11.23) at genome-wide significance. Four of the index single nucleotide polymorphisms (SNPs) lie within introns of genes (KCNK2, C5orf56, SCAMP2, and SIN3A) and the other index SNPs are located close to GSTM4, AMPD2, CASTOR2, and RP11-168G16.2. Here we present risk loci with consistent direction of associations in African and European descendants. The study suggests that replication across multiple ancestry populations can help improve the understanding of breast cancer genetics and identify causal variants.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Neoplasias da Mama/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Locos de Características Quantitativas , Feminino , Estudo de Associação Genômica Ampla , Humanos , Íntrons , Polimorfismo de Nucleotídeo Único
15.
Int J Mol Sci ; 22(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198491

RESUMO

Rare germline pathogenic TP53 missense variants often predispose to a wide spectrum of tumors characterized by Li-Fraumeni syndrome (LFS) but a subset of variants is also seen in families with exclusively hereditary breast cancer (HBC) outcomes. We have developed a logistic regression model with the aim of predicting LFS and HBC outcomes, based on the predicted effects of individual TP53 variants on aspects of protein conformation. A total of 48 missense variants either unique for LFS (n = 24) or exclusively reported in HBC (n = 24) were included. LFS-variants were over-represented in residues tending to be buried in the core of the tertiary structure of TP53 (p = 0.0014). The favored logistic regression model describes disease outcome in terms of explanatory variables related to the surface or buried status of residues as well as their propensity to contribute to protein compactness or protein-protein interactions. Reduced, internally validated models discriminated well between LFS and HBC (C-statistic = 0.78-0.84; equivalent to the area under the ROC (receiver operating characteristic) curve), had a low risk for over-fitting and were well calibrated in relation to the known outcome risk. In conclusion, this study presents a phenotypic prediction model of LFS and HBC risk for germline TP53 missense variants, in an attempt to provide a complementary tool for future decision making and clinical handling.


Assuntos
Neoplasias da Mama/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Síndrome de Li-Fraumeni/genética , Mutação de Sentido Incorreto/genética , Proteína Supressora de Tumor p53/química , Proteína Supressora de Tumor p53/genética , Sequência de Aminoácidos , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Modelos Logísticos , Análise Multivariada , Fenótipo , Conformação Proteica
16.
Breast Cancer Res Treat ; 189(1): 49-61, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34196902

RESUMO

PURPOSE: Breast cancer remains a prominent global disease affecting women worldwide despite the emergence of novel therapeutic regimens. Metastasis is responsible for most cancer-related deaths, and acquisition of a mesenchymal and migratory cancer cell phenotypes contributes to this devastating disease. The utilization of kinase targets in drug discovery have revolutionized the field of cancer research but despite impressive advancements in kinase-targeting drugs, a large portion of the human kinome remains understudied in cancer. NEK5, a member of the Never-in-mitosis kinase family, is an example of such an understudied kinase. Here, we characterized the function of NEK5 in breast cancer. METHODS: Stably overexpressing NEK5 cell lines (MCF7) and shRNA knockdown cell lines (MDA-MB-231, TU-BcX-4IC) were utilized. Cell morphology changes were evaluated using immunofluorescence and quantification of cytoskeletal components. Cell proliferation was assessed by Ki-67 staining and transwell migration assays tested cell migration capabilities. In vivo experiments with murine models were necessary to demonstrate NEK5 function in breast cancer tumor growth and metastasis. RESULTS: NEK5 activation altered breast cancer cell morphology and promoted cell migration independent of effects on cell proliferation. NEK5 overexpression or knockdown does not alter tumor growth kinetics but promotes or suppresses metastatic potential in a cell type-specific manner, respectively. CONCLUSION: While NEK5 activity modulated cytoskeletal changes and cell motility, NEK5 activity affected cell seeding capabilities but not metastatic colonization or proliferation in vivo. Here we characterized NEK5 function in breast cancer systems and we implicate NEK5 in regulating specific steps of metastatic progression.


Assuntos
Neoplasias da Mama , Animais , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Feminino , Humanos , Camundongos , Quinases Relacionadas a NIMA/genética , Fenótipo , RNA Interferente Pequeno
17.
Breast Cancer Res Treat ; 189(1): 25-37, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34231077

RESUMO

PURPOSE: The transcription factors ZEB1 and ZEB2 mediate epithelial-to-mesenchymal transition (EMT) and metastatic progression in numerous malignancies including breast cancer. ZEB1 and ZEB2 drive EMT through transcriptional repression of cell-cell junction proteins and members of the tumor suppressive miR200 family. However, in estrogen receptor positive (ER +) breast cancer, the role of ZEB2 as an independent driver of metastasis has not been fully investigated. METHODS: In the current study, we induced exogenous expression of ZEB2 in ER + MCF-7 and ZR-75-1 breast cancer cell lines and examined EMT gene expression and metastasis using dose-response qRT-PCR, transwell migration assays, proliferation assays with immunofluorescence of Ki-67 staining. We used RNA sequencing to identify pathways and genes affected by ZEB2 overexpression. Finally, we treated ZEB2-overexpressing cells with 17ß-estradiol (E2) or ICI 182,780 to evaluate how ZEB2 affects estrogen response. RESULTS: Contrary to expectation, we found that ZEB2 did not increase canonical epithelial nor decrease mesenchymal gene expressions. Furthermore, ZEB2 overexpression did not promote a mesenchymal cell morphology. However, ZEB1 and ZEB2 protein expression induced significant migration of MCF-7 and ZR-75-1 breast cancer cells in vitro and MCF-7 xenograft metastasis in vivo. Transcriptomic (RNA sequencing) pathway analysis revealed alterations in estrogen signaling regulators and pathways, suggesting a role for ZEB2 in endocrine sensitivity in luminal A breast cancer. Expression of ZEB2 was negatively correlated with estrogen receptor complex genes in luminal A patient tumors. Furthermore, treatment with 17ß-estradiol (E2) or the estrogen receptor antagonist ICI 182,780 had no effect on growth of ZEB2-overexpressing cells. CONCLUSION: ZEB2 is a multi-functional regulator of drug sensitivity, cell migration, and metastasis in ER + breast cancer and functions through non-canonical mechanisms.


Assuntos
Neoplasias da Mama , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Movimento Celular , Transição Epitelial-Mesenquimal/genética , Feminino , Fulvestranto , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética
18.
Nat Commun ; 12(1): 4308, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262028

RESUMO

Hypoxia plays a critical role in tumor progression including invasion and metastasis. To determine critical genes regulated by hypoxia that promote invasion and metastasis, we screen fifty hypoxia inducible genes for their effects on invasion. In this study, we identify v-maf musculoaponeurotic fibrosarcoma oncogene homolog F (MAFF) as a potent regulator of tumor invasion without affecting cell viability. MAFF expression is elevated in metastatic breast cancer patients and is specifically correlated with hypoxic tumors. Combined ChIP- and RNA-sequencing identifies IL11 as a direct transcriptional target of the heterodimer between MAFF and BACH1, which leads to activation of STAT3 signaling. Inhibition of IL11 results in similar levels of metastatic suppression as inhibition of MAFF. This study demonstrates the oncogenic role of MAFF as an activator of the IL11/STAT3 pathways in breast cancer.


Assuntos
Neoplasias da Mama/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Interleucina-11/metabolismo , Fator de Transcrição MafF/metabolismo , Proteínas Nucleares/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Hipóxia Celular , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Fator de Transcrição MafF/genética , Camundongos , Invasividade Neoplásica/patologia , Metástase Neoplásica/patologia , Proteínas Nucleares/genética , Prognóstico , Transdução de Sinais , Transcrição Genética
19.
BMC Bioinformatics ; 22(1): 300, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34082714

RESUMO

BACKGROUND: Accurate prognosis and identification of cancer subtypes at molecular level are important steps towards effective and personalised treatments of breast cancer. To this end, many computational methods have been developed to use gene (mRNA) expression data for breast cancer subtyping and prognosis. Meanwhile, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) have been extensively studied in the last 2 decades and their associations with breast cancer subtypes and prognosis have been evidenced. However, it is not clear whether using miRNA and/or lncRNA expression data helps improve the performance of gene expression based subtyping and prognosis methods, and this raises challenges as to how and when to use these data and methods in practice. RESULTS: In this paper, we conduct a comparative study of 35 methods, including 12 breast cancer subtyping methods and 23 breast cancer prognosis methods, on a collection of 19 independent breast cancer datasets. We aim to uncover the roles of miRNAs and lncRNAs in breast cancer subtyping and prognosis from the systematic comparison. In addition, we created an R package, CancerSubtypesPrognosis, including all the 35 methods to facilitate the reproducibility of the methods and streamline the evaluation. CONCLUSIONS: The experimental results show that integrating miRNA expression data helps improve the performance of the mRNA-based cancer subtyping methods. However, miRNA signatures are not as good as mRNA signatures for breast cancer prognosis. In general, lncRNA expression data does not help improve the mRNA-based methods in both cancer subtyping and cancer prognosis. These results suggest that the prognostic roles of miRNA/lncRNA signatures in the improvement of breast cancer prognosis needs to be further verified.


Assuntos
Neoplasias da Mama , MicroRNAs , RNA Longo não Codificante , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , MicroRNAs/genética , RNA Longo não Codificante/genética , Reprodutibilidade dos Testes
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