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1.
Anticancer Res ; 39(10): 5361-5367, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570430

RESUMO

BACKGROUND/AIM: The mechanism responsible for B-cell translocation gene 1 (BTG1) down-regulation in breast carcinoma remains unknown. We examined the BTG1 expression status in breast carcinoma cells and investigated the mechanism underlying the observed alterations. MATERIALS AND METHODS: Four breast carcinoma cell lines (SK-BR-3, MDA-MB-231, T-47D, and MCF-7), and one normal mammary epithelial cell line (MCF-10A) were analyzed. BTG1 expression was examined using quantitative reverse transcription polymerase chain reaction (PCR) and western blot. Methylation status of the BTG1 promoter was analyzed using methylation-specific PCR (MSP). To investigate the effect of methylation on BTG1, the cells were treated with a demethylating agent. RESULTS: The carcinoma cells expressed significantly lower levels of BTG1 mRNA and protein than normal cells. The BTG1 promoter was highly methylated in the carcinoma cells. 5-aza-2-deoxycytidine significantly restored BTG1 expression. CONCLUSION: Down-regulation of BTG1 expression through epigenetic repression is involved in mammary carcinogenesis. BTG1 is a potential diagnostic marker and therapeutic target for breast carcinoma.


Assuntos
Neoplasias da Mama/genética , Metilação de DNA/genética , Regulação para Baixo/genética , Proteínas de Neoplasias/genética , Regiões Promotoras Genéticas/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Epigênese Genética/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Células MCF-7 , RNA Mensageiro/genética
2.
Anticancer Res ; 39(10): 5653-5662, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570463

RESUMO

BACKGROUND/AIM: Factors influencing fulvestrant efficacy may be useful in selecting the optimal treatment regimen for postmenopausal Japanese women with metastatic/recurrent HR-positive, HER2-negative breast cancer. PATIENTS AND METHODS: We retrospectively evaluated progression-free and overall survival (PFS and OS) in 100 fulvestrant-treated patients according to metastatic site. RESULTS: Median PFS was significantly better in patients with non-visceral (bone and regional metastases; 22.8 months) vs. visceral metastasis (lung, liver, and other organs; 8.2 months; p=0.024), although median OS did not differ (p=0.922). Median PFS in patients with lung metastasis (20.8 months) and non-visceral metastasis (22.8 months) were comparable; patients with liver metastasis (6.1 months) and other organ metastases (3.7 months) had worse prognoses. CONCLUSION: Patients with non-visceral metastases had a better prognosis than those with visceral metastases. Fulvestrant induced a longer PFS in patients with non-visceral metastasis, and also in those with lung metastasis without liver or other organ involvement.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Fulvestranto/uso terapêutico , Metástase Neoplásica/prevenção & controle , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , Intervalo Livre de Progressão , Receptor ErbB-2/genética , Receptores de Superfície Celular/genética , Estudos Retrospectivos
3.
JAMA ; 322(9): 868-886, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31479143

RESUMO

Importance: Medications to reduce risk of breast cancer are effective for women at increased risk but also cause adverse effects. Objective: To update the 2013 US Preventive Services Task Force systematic review on medications to reduce risk of primary (first diagnosis) invasive breast cancer in women. Data Sources: Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, EMBASE, and MEDLINE (January 1, 2013, to February 1, 2019); manual review of reference lists. Study Selection: Discriminatory accuracy studies of breast cancer risk assessment methods; randomized clinical trials of tamoxifen, raloxifene, and aromatase inhibitors for primary breast cancer prevention; studies of medication adverse effects. Data Extraction and Synthesis: Investigators abstracted data on methods, participant characteristics, eligibility criteria, outcome ascertainment, and follow-up. Results of individual trials were combined by using a profile likelihood random-effects model. Main Outcomes and Measures: Probability of breast cancer in individuals (area under the receiver operating characteristic curve [AUC]); incidence of breast cancer, fractures, thromboembolic events, coronary heart disease events, stroke, endometrial cancer, and cataracts; and mortality. Results: A total of 46 studies (82 articles [>5 million participants]) were included. Eighteen risk assessment methods in 25 studies reported low accuracy in predicting the probability of breast cancer in individuals (AUC, 0.55-0.65). In placebo-controlled trials, tamoxifen (risk ratio [RR], 0.69 [95% CI, 0.59-0.84]; 4 trials [n = 28 421]), raloxifene (RR, 0.44 [95% CI, 0.24-0.80]; 2 trials [n = 17 806]), and the aromatase inhibitors exemestane and anastrozole (RR, 0.45 [95% CI, 0.26-0.70]; 2 trials [n = 8424]) were associated with a lower incidence of invasive breast cancer. Risk for invasive breast cancer was higher for raloxifene than tamoxifen in 1 trial after long-term follow-up (RR, 1.24 [95% CI, 1.05-1.47]; n = 19 747). Raloxifene was associated with lower risk for vertebral fractures (RR, 0.61 [95% CI, 0.53-0.73]; 2 trials [n = 16 929]) and tamoxifen was associated with lower risk for nonvertebral fractures (RR, 0.66 [95% CI, 0.45-0.98]; 1 trial [n = 13 388]) compared with placebo. Tamoxifen and raloxifene were associated with increased thromboembolic events compared with placebo; tamoxifen was associated with more events than raloxifene. Tamoxifen was associated with higher risk of endometrial cancer and cataracts compared with placebo. Symptomatic effects (eg, vasomotor, musculoskeletal) varied by medication. Conclusions and Relevance: Tamoxifen, raloxifene, and aromatase inhibitors were associated with lower risk of primary invasive breast cancer in women but also were associated with adverse effects that differed between medications. Risk stratification methods to identify patients with increased breast cancer risk demonstrated low accuracy.


Assuntos
Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/prevenção & controle , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Tamoxifeno/uso terapêutico , Adulto , Área Sob a Curva , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/genética , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Mutação , Guias de Prática Clínica como Assunto , Cloridrato de Raloxifeno/efeitos adversos , Cloridrato de Raloxifeno/uso terapêutico , Medição de Risco/métodos , Fatores de Risco , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Tamoxifeno/efeitos adversos
4.
JAMA ; 322(9): 857-867, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31479144

RESUMO

Importance: Breast cancer is the most common nonskin cancer among women in the United States and the second leading cause of cancer death. The median age at diagnosis is 62 years, and an estimated 1 in 8 women will develop breast cancer at some point in their lifetime. African American women are more likely to die of breast cancer compared with women of other races. Objective: To update the 2013 US Preventive Services Task Force (USPSTF) recommendation on medications for risk reduction of primary breast cancer. Evidence Review: The USPSTF reviewed evidence on the accuracy of risk assessment methods to identify women who could benefit from risk-reducing medications for breast cancer, as well as evidence on the effectiveness, adverse effects, and subgroup variations of these medications. The USPSTF reviewed evidence from randomized trials, observational studies, and diagnostic accuracy studies of risk stratification models in women without preexisting breast cancer or ductal carcinoma in situ. Findings: The USPSTF found convincing evidence that risk assessment tools can predict the number of cases of breast cancer expected to develop in a population. However, these risk assessment tools perform modestly at best in discriminating between individual women who will or will not develop breast cancer. The USPSTF found convincing evidence that risk-reducing medications (tamoxifen, raloxifene, or aromatase inhibitors) provide at least a moderate benefit in reducing risk for invasive estrogen receptor-positive breast cancer in postmenopausal women at increased risk for breast cancer. The USPSTF found that the benefits of taking tamoxifen, raloxifene, and aromatase inhibitors to reduce risk for breast cancer are no greater than small in women not at increased risk for the disease. The USPSTF found convincing evidence that tamoxifen and raloxifene and adequate evidence that aromatase inhibitors are associated with small to moderate harms. Overall, the USPSTF determined that the net benefit of taking medications to reduce risk of breast cancer is larger in women who have a greater risk for developing breast cancer. Conclusions and Recommendation: The USPSTF recommends that clinicians offer to prescribe risk-reducing medications, such as tamoxifen, raloxifene, or aromatase inhibitors, to women who are at increased risk for breast cancer and at low risk for adverse medication effects. (B recommendation) The USPSTF recommends against the routine use of risk-reducing medications, such as tamoxifen, raloxifene, or aromatase inhibitors, in women who are not at increased risk for breast cancer. (D recommendation) This recommendation applies to asymptomatic women 35 years and older, including women with previous benign breast lesions on biopsy (such as atypical ductal or lobular hyperplasia and lobular carcinoma in situ). This recommendation does not apply to women who have a current or previous diagnosis of breast cancer or ductal carcinoma in situ.


Assuntos
Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/prevenção & controle , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Tamoxifeno/uso terapêutico , Adulto , Neoplasias da Mama/genética , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Pessoa de Meia-Idade , Mutação , Cloridrato de Raloxifeno/uso terapêutico , Medição de Risco/métodos , Fatores de Risco
5.
Anticancer Res ; 39(9): 4957-4963, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519601

RESUMO

BACKGROUND/AIM: Adjuvant radiotherapy (RT) damages multiple layers of skin, muscle, blood vessels and blood cells that are included within the RT area. Indirect, bystander systemic effects could also develop in cells not directly hit by radiation. MATERIALS AND METHODS: Ninety-three female patients recovering from breast cancer surgery and 82 female healthy blood donors were analyzed. For identification of systemic adaptive and innate immune response, rapid and low-cost blood-based biomarkers were assayed. RESULTS: Post-operated breast cancer patients had a decreased number of circulating adaptive immune response cells but increased number of circulating immunosuppressive myeloid subpopulations. RT decreased the number of T-cells and platelets without influencing the number of immunosuppressive myeloid subpopulations. Alterations in the number and phenotypes of T-cell subpopulations were associated with SNPs. CONCLUSION: The combination of RT and immunotherapy might provide optimal treatment for cancer patients.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Imunidade Celular/genética , Imunidade Celular/efeitos da radiação , Contagem de Leucócitos , Fenótipo , Polimorfismo de Nucleotídeo Único , Imunidade Adaptativa , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Estudos de Casos e Controles , Feminino , Humanos , Imunidade Inata , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Radioterapia Adjuvante , Linfócitos T/imunologia , Linfócitos T/metabolismo
6.
Medicine (Baltimore) ; 98(37): e17135, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31517852

RESUMO

RATIONALE: In estrogen receptor-positive HER2-negative (ER+HER2-) metastatic breast cancer, chemotherapy should be offered only to patients who develop endocrine resistance or have a rapid disease progression. However, the correct sequence of chemotherapy administration is still debated. PATIENT CONCERNS: We report the case of a 49-year-old woman with ER+ HER2- metastatic breast cancer who experienced an exceptionally long response to capecitabine administered as second-line therapy following a first-line anthracycline-based chemotherapy. DIAGNOSES: The patient was diagnosed with ER+ HER2- metastatic breast cancer with massive liver involvement and mediastinal lymph nodes metastasis. INTERVENTIONS: This patient was treated with capecitabine 1000 mg/mq bid given intermittently for 14 days within a 21-day cycle as a second-line therapy following a rapid progression on letrozole treatment given as a maintenance therapy. OUTCOMES: Our patient experienced a progression-free survival (PFS) >3 years with an exceptionally good quality of life (QoL). LESSONS: In ER+HER2- metastatic breast cancer patients, capecitabine monochemotherapy in second line may be associated with a particularly satisfactory PFS and no impact in terms of QoL. Future studies focused on biomarkers with predictive ability may help select patients who represent the best candidates to this treatment.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Capecitabina/uso terapêutico , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/patologia , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Feminino , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Metástase Linfática/genética , Pessoa de Meia-Idade , Receptores Estrogênicos/genética
7.
Adv Exp Med Biol ; 1152: 9-29, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456177

RESUMO

Epidemiologic studies have contributed importantly to current knowledge of environmental and genetic risk factors for breast cancer. Worldwide, breast cancer is an important cause of human suffering and premature mortality among women. In the United States, breast cancer accounts for more cancer deaths in women than any site other than lung cancer. A variety of risk factors for breast cancer have been well-established by epidemiologic studies including race, ethnicity, family history of cancer, and genetic traits, as well as modifiable exposures such as increased alcohol consumption, physical inactivity, exogenous hormones, and certain female reproductive factors. Younger age at menarche, parity, and older age at first full-term pregnancy may influence breast cancer risk through long-term effects on sex hormone levels or by other biological mechanisms. Recent studies have suggested that triple negative breast cancers may have a distinct etiology. Genetic variants and mutations in genes that code for proteins having a role in DNA repair pathways and the homologous recombination of DNA double stranded breaks (APEX1, BRCA1, BRCA2, XRCC2, XRCC3, ATM, CHEK2, PALB2, RAD51, XPD), have been implicated in some cases of breast cancer.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Proteínas de Ligação a DNA/genética , Feminino , Predisposição Genética para Doença , Recombinação Homóloga , Humanos , Mutação , Gravidez , Neoplasias de Mama Triplo Negativas/epidemiologia , Neoplasias de Mama Triplo Negativas/etiologia
8.
Adv Exp Med Biol ; 1152: 229-241, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456186

RESUMO

A large proportion of breast cancer patients are estrogen receptor positive. They generally benefit from tamoxifen, the drug that targets estrogen receptor signaling. However, de novo and acquired resistance against tamoxifen is well known. A number of signaling pathways and de-regulated factors have been evaluated to better understand the mechanism(s) of tamoxifen resistance. For past several years, non-coding RNAs have also gained attention as the putative regulators and determinants of tamoxifen resistance. A number of reports have documented evidence from in vitro and/or in vivo studies, as well as from evaluation of clinical samples, to showcase the power of non-coding RNAs as mediators of tamoxifen resistance and the predictors of disease relapse. This article puts into perspective the available information on microRNAs and the long non-coding RNAs regarding their ability to tweak resistance vs. sensitivity to tamoxifen.


Assuntos
Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Tamoxifeno/farmacologia , Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos
9.
Adv Exp Med Biol ; 1152: 243-252, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456187

RESUMO

Sequencing technologies have allowed us to characterize highly heterogeneous molecular landscape of breast cancer with unprecedented details. Tremendous breakthroughs have been made in unraveling contributory role of signaling pathways in breast cancer development and progression. It is becoming progressively more understandable that deregulation of spatio-temporally controlled pathways underlie development of resistance against different drugs. TRAIL mediated signaling has attracted considerable appreciation because of its characteristically unique ability to target cancer cells while leaving normal cells intact. Discovery of TRAIL was considered as a paradigm shift in molecular oncology because of its conspicuous ability to selectively target cancer cells. There was an exponential growth in the number of high-quality reports which highlighted cancer targeting ability of TRAIL and scientists worked on the development of TRAIL-based therapeutics and death receptor targeting agonistic antibodies to treat cancer. However, later studies challenged simplistic view related to tumor targeting ability of TRAIL. Detailed mechanistic insights revealed that overexpression of anti-apoptotic proteins, inactivation of pro-apoptotic proteins and downregulation of death receptors were instrumental in impairing apoptosis in cancer cells. Therefore researchers started to give attention to identification of methodologies and strategies to overcome the stumbling blocks associated with TRAIL-based therapeutics. Subsequent studies gave us a clear picture of signaling cascade of TRAIL and how deregulation of different proteins abrogated apoptosis. In this chapter we have attempted to provide an overview of the TRAIL induced signaling, list of proteins frequently deregulated and modern approaches to strategically restore apoptosis in TRAIL-resistant breast cancers.


Assuntos
Apoptose , Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos , Transdução de Sinais , Ligante Indutor de Apoptose Relacionado a TNF/genética , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Feminino , Humanos
10.
Adv Exp Med Biol ; 1152: 293-310, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456191

RESUMO

Epigenetics refers to alterations in gene expression due to differential histone modifications and DNA methylation at promoter sites of genes. Epigenetic alterations are reversible and are heritable during somatic cell division, but do not involve changes in nucleotide sequence. Epigenetic regulation plays a critical role in normal growth and embryonic development by controlling transcriptional activities of several genes. In last two decades, these modifications have been well recognized to be involved in tumor initiation and progression, which has motivated many investigators to incorporate this novel field in cancer drug development. Recently, growing number of epigenetic changes have been reported that are involved in the regulations of genes involved in breast tumor growth and metastasis. Drugs possessing epigenetic modulatory activities known as epi-drugs, mainly the inhibitors of histone deacetylases (HDACs) and DNA methyltransferases (DNMTs). Some of these drugs are undergoing different clinical trials for breast cancer treatment. Several phytochemicals such as green tea polyphenols, curcumin, genistein, resveratrol and sulforaphane have also been shown to alter epigenetic modifications in multiple cancer types including breast cancer. In this chapter, we summarize the role of epigenetic changes in breast cancer progression and metastasis. We have also discussed about various epigenetic modulators possessing chemopreventive and therapeutic efficacy against breast cancer with future perspectives.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Epigênese Genética , DNA (Citosina-5-)-Metiltransferase 1/antagonistas & inibidores , Metilação de DNA , Feminino , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases , Humanos , Compostos Fitoquímicos/farmacologia
11.
Adv Exp Med Biol ; 1152: 335-364, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456193

RESUMO

Breast cancer and specifically metastatic breast cancer (mBC) constitutes a major health burden worldwide with the highest number of cancer-related mortality among women across the globe. Despite having similar subtypes, breast cancer patients present with a spectrum of aggressiveness and responsiveness to therapy due to cancer heterogeneity. Drug resistance and metastasis contribute to therapy failure and cancer recurrence. Research in the past two decades has focused on microRNAs (miRNAs), small endogenous non-coding RNAs, as active players in tumorigenesis, therapy resistance and metastasis and as novel non-invasive cancer biomarkers. This is due to their unique dysregulated signatures throughout tumor progression and their tumor suppressive/oncogenic roles. Identifying miRNAs signatures capable of predicting therapy response and metastatic onset in breast cancer patients might improve prognosis and offer prolonged median and relapse-free survival rate. Despite the growing reports on miRNAs as novel non-invasive biomarkers in breast cancer and as regulators of breast cancer drug resistance or metastasis, the quest on whether some miRNAs are capable of regulating both simultaneously is inevitable, yet understudied. This chapter will review the role of miRNAs as biomarkers and as active players in inducing/reversing anti-cancer drug resistance, driving/blocking metastasis or regulating both simultaneously in breast cancer.


Assuntos
Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos , MicroRNAs/genética , Metástase Neoplásica , Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Recidiva Local de Neoplasia
12.
Adv Exp Med Biol ; 1152: 365-375, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456194

RESUMO

Massively parallel sequencing, genomic and proteomic technologies have provided near complete resolution of signaling landscape of breast cancer (BCa). NEDD4 family of E3-ubiquitin ligases comprises a large family of proteins particularly, SMURFs (SMURF1, SMURF2), WWPs and NEDD4 which are ideal candidates for targeted therapy. However, it is becoming progressively more understandable that SMURFs and NEDD4 have "split-personalities". These molecules behave dualistically in breast cancer and future studies must converge on detailed identification of context specific role of these proteins in BCa. Finally, we provide scattered clues of regulation of SMURF2 by oncogenic miRNAs, specifically considering longstanding questions related to regulation of SMURF1 and WWPs by miRNAs in BCa. SMURFS, WWPs and NEDD4 are versatile regulators and represent a fast-growing field in cancer research and better understanding of the underlying mechanisms will be helpful in transition of our knowledge from a segmented view to a more conceptual continuum.


Assuntos
Neoplasias da Mama/enzimologia , Ubiquitina-Proteína Ligases Nedd4/genética , Ubiquitina-Proteína Ligases/genética , Neoplasias da Mama/genética , Feminino , Humanos , MicroRNAs/genética , Oncogenes , Proteômica , Transdução de Sinais , Ubiquitinação
13.
Tumour Biol ; 41(8): 1010428319869096, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31405342

RESUMO

Variable association of transforming growth factor beta 1 (TGFß1) in breast cancer (BC) pathogenesis was documented, and the contribution of specific TGFB1 polymorphisms to the progression of BC and associated features remains poorly understood. We investigated the contribution of TGFB1 rs1800469, rs1800470, rs1800471, and rs1800472 variants and 4-locus TGFB1 haplotypes on BC susceptibility, and pathological presentation of BC subtypes. Study subjects comprised 430 female BC cases, and 498 cancer-free control women. BC-associated pathological parameters were also evaluated for correlation with TGFB1 variants. Results obtained showed that the minor allele frequency (MAF) of rs1800471 (+74G>C) was higher seen in BC cases than in control subjects, and was associated with increased risk of BC. Significant differences in rs1800471 and rs1800469 (-509C>T) genotype distribution were noted between BC cases and controls, which persisted after controlling for key covariates. TGFB1 rs1800472 was positively, while rs1800470 was negatively associated with triple negativity, while rs1800470 positively correlated with menarche, but negatively with tumor size and molecular type, and rs1800469 correlated positively with menstrual irregularity, distant metastasis, nodal status, and hormonotherapy. Heterogeneity in LD pattern was noted between the tested TGFB1 variants. Four-locus (rs1800472-rs1800471-rs1800470-rs1800469) Haploview analysis identified haplotype TGCT to be negatively associated, and haplotypes CGTT and CCCC to be positively associated with BC. This association of CGTT and CCCC, but not TGCT, with BC remained significant after controlling for key covariates. In conclusion, TGFB1 alleles and specific genotypes, and 4-locus TGFB1 haplotypes influence BC susceptibility, suggesting dual association imparted by specific SNP, consistent with dual role for TGFB1 in BC pathogenesis.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Haplótipos/genética , Polimorfismo de Nucleotídeo Único/genética , Fator de Crescimento Transformador beta1/genética , Alelos , Feminino , Frequência do Gene/genética , Humanos , Pessoa de Meia-Idade , Tunísia
14.
Anticancer Res ; 39(8): 4031-4041, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366485

RESUMO

BACKGROUND/AIM: Eribulin is currently used to treat advanced and metastatic breast cancer in the clinical setting; however, its efficacy is inhibited by resistance acquisition in many cases. Thus, the present study established two eribulin-resistant breast-cancer cell lines, and used these to investigate the mechanisms that underly eribulin-resistance acquisition. MATERIALS AND METHODS: Eribulin-resistant breast-cancer cell lines were generated by culturing MDA-MB-231 and MCF-7 cells with increasing concentrations of eribulin. RESULTS: The eribulin-resistant cells acquired resistance to eribulin, as well as several other anticancer drugs. After eribulin treatment, the eribulin-resistant cell lines showed no morphological change, no increased expression of epithelial-cadherin, nor any significant alteration in cell-cycle distribution. In contrast, the expression levels of programmed death-ligand 1 were increased in the MCF-7/eribulin-resistant compared to MCF-7 cells. CONCLUSION: The herein developed eribulin-resistant cell lines acquired cross-resistance to various anticancer agents, and displayed resistance to eribulin-induced effects on microtubule function and epithelial-mesenchymal transition (EMT).


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Furanos/administração & dosagem , Cetonas/administração & dosagem , Animais , Antineoplásicos/efeitos adversos , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Furanos/efeitos adversos , Humanos , Cetonas/efeitos adversos , Células MCF-7 , Camundongos , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Life Sci ; 234: 116756, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31419444

RESUMO

AIMS: Conventional radiotherapy is mainly restricted by the low radiation absorption efficiency of tumors tissues and the hypoxic tumor cells radio-resistance. In this paper, novel nano-radiosensitizers, magnetic nanoparticles core coated with silica, were successfully prepared to overcome these limitations. MAIN METHODS: The prepared nanoparticles have been characterized by transmission electron microscope (TEM), Dynamic light scattering (DLS), atomic force microscope (AFM) and vibration sample magnetometer (VSM). MTT cytotoxicity and DNA double-strand breaks (Comet) assays have been used to assess the radio-enhancing effect of iron oxide magnetic nanoparticles (IO-MNPs) and silica-coated iron oxide magnetic nanoparticles (SIO-MNPs) against MCF7 breast cancer cells. MCF7 cells were treated with different concentrations of the prepared nanoformulations and exposed to an electron beam at doses 0, 0.5, 1, 2, 4 Gy. KEY FINDINGS: DLS measurements revealed that the main hydrodynamic diameter of the prepared IO-MNPs and SIO-MNPs was 18.17 ±â€¯4.5 nm and 164.18 ±â€¯16.1 nm, respectively, which was confirmed by TEM micrographs. MTT and comet assays results showed that the radiosensitizing effect of the prepared nanoformulations was dose and concentration dependent. Interestingly, the dose enhancement factor (DEF) for SIO-MNPs was, on average, 1.3-fold greater than that of IO-MNPs. SIGNIFICANCE: Coating of IO-MNPs with silica led to enhance their electron radiosensitization and consequently their therapeutic efficacy. Therefore, SIO-MNPs represent a promising engineered nano-formulation for enhancing breast cancer radiosensitivity.


Assuntos
Neoplasias da Mama/radioterapia , Compostos Férricos/uso terapêutico , Nanopartículas/uso terapêutico , Radiossensibilizantes/uso terapêutico , Dióxido de Silício/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Sobrevivência Celular/efeitos da radiação , Dano ao DNA/efeitos da radiação , Elétrons , Feminino , Compostos Férricos/química , Humanos , Células MCF-7 , Nanopartículas/química , Radiossensibilizantes/química , Dióxido de Silício/química
16.
Zhonghua Zhong Liu Za Zhi ; 41(8): 587-593, 2019 Aug 23.
Artigo em Chinês | MEDLINE | ID: mdl-31434449

RESUMO

Objective: To assess the association of single nucleotide polymorphisms (SNPs) in SLCO1B3 gene with prognosis of breast cancer (BC) patients treated with neoadjuvant chemotherapy of TA regimen (taxane and antharcycline drugs). Methods: 439 female BC patients were recruited and treated with neoadjuvant chemotherapy of TA regimen. A blood sample (2 ml) of peripheral blood was collected from each patient before chemotherapy. Tagging SNPs (tag-SNPs) were selected. We investigated the association of tag-SNPs with prognosis, by Sequenom Mass ARRAY system platform, characterizing tag-SNPs. The hazard ratio (HR) and 95% confidence interval (CI) for progression or death were calculated by multivariable-adjusted Cox regression model. Results: Seven tag-SNPs (rs11045689, rs200104106, rs3764006, rs3834935, rs4149117, rs7305323 and rs73241801) were selected for study. Compared with individuals carrying the rs11045689 GG genotype, individuals carrying rs11045689 AA genotype performed worse PFS and OS, with the HR (95% CI) for progression being 1.39 (1.11~1.75) and the HR (95% CI) for death being 1.38 (1.04~1.83). Compared with individuals carrying the rs73241801 CC genotype, individuals carrying rs73241801 TT genotype performed better OS (P=0.041), with the HR (95% CI) for death being 0.65 (0.44~0.94). The number of risk allele was significantly associated with PFS (P=0.012) and OS (P=0.017) of BC patients by accumulation analysis. Compared with individuals carrying one or less than one risk allele, individuals carrying four risk alleles performed worse PFS and OS, with the HR (95% CI) for progression being 1.37 (1.09~1.72) and the HR (95% CI) for death being 1.36 (1.02~1.81). Conclusion: The variations of rs11045689 and rs73241801 in SLCO1B3 gene were significantly associated with prognosis of BC patients treated with neoadjuvant chemotherapy of TA regimen, which might serve as biomarkers for predicting prognosis of BC patients treated with neoadjuvant chemotherapy.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/genética , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Feminino , Genótipo , Humanos , Terapia Neoadjuvante , Polimorfismo de Nucleotídeo Único , Prognóstico , Taxoides/uso terapêutico
18.
JAMA ; 322(7): 666-685, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31429902

RESUMO

Importance: Pathogenic mutations in breast cancer susceptibility genes BRCA1 and BRCA2 increase risks for breast, ovarian, fallopian tube, and peritoneal cancer in women; interventions reduce risk in mutation carriers. Objective: To update the 2013 US Preventive Services Task Force review on benefits and harms of risk assessment, genetic counseling, and genetic testing for BRCA1/2-related cancer in women. Data Sources: Cochrane libraries; MEDLINE, PsycINFO, EMBASE (January 1, 2013, to March 6, 2019, for updates; January 1, 1994, to March 6, 2019, for new key questions and populations); reference lists. Study Selection: Discriminatory accuracy studies, randomized clinical trials (RCTs), and observational studies of women without recently diagnosed BRCA1/2-related cancer. Data Extraction and Synthesis: Data on study methods, setting, population characteristics, eligibility criteria, interventions, numbers enrolled and lost to follow-up, outcome ascertainment, and results were abstracted. Two reviewers independently assessed study quality. Main Outcomes and Measures: Cancer incidence and mortality; discriminatory accuracy of risk assessment tools for BRCA1/2 mutations; benefits and harms of risk assessment, genetic counseling, genetic testing, and risk-reducing interventions. Results: For this review, 103 studies (110 articles; N = 92 712) were included. No studies evaluated the effectiveness of risk assessment, genetic counseling, and genetic testing in reducing incidence and mortality of BRCA1/2-related cancer. Fourteen studies (n = 43 813) of 8 risk assessment tools to guide referrals to genetic counseling demonstrated moderate to high accuracy (area under the receiver operating characteristic curve, 0.68-0.96). Twenty-eight studies (n = 8060) indicated that genetic counseling was associated with reduced breast cancer worry, anxiety, and depression; increased understanding of risk; and decreased intention for testing. Twenty studies (n = 4322) showed that breast cancer worry and anxiety were higher after testing for women with positive results and lower for others; understanding of risk was higher after testing. In 8 RCTs (n = 54 651), tamoxifen (relative risk [RR], 0.69 [95% CI, 0.59-0.84]; 4 trials), raloxifene (RR, 0.44 [95% CI, 0.24-0.80]; 2 trials), and aromatase inhibitors (RR, 0.45 [95% CI, 0.26-0.70]; 2 trials) were associated with lower risks of invasive breast cancer compared with placebo; results were not specific to mutation carriers. Mastectomy was associated with 90% to 100% reduction in breast cancer incidence (6 studies; n = 2546) and 81% to 100% reduction in breast cancer mortality (1 study; n = 639); oophorectomy was associated with 69% to 100% reduction in ovarian cancer (2 studies; n = 2108); complications were common with mastectomy. Conclusions and Relevance: Among women without recently diagnosed BRCA1/2-related cancer, the benefits and harms of risk assessment, genetic counseling, and genetic testing to reduce cancer incidence and mortality have not been directly evaluated by current research.


Assuntos
Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Aconselhamento Genético , Testes Genéticos , Mutação , Neoplasias Ovarianas/genética , Neoplasias da Mama/prevenção & controle , Neoplasias das Tubas Uterinas/genética , Neoplasias das Tubas Uterinas/prevenção & controle , Feminino , Predisposição Genética para Doença , Humanos , Neoplasias Ovarianas/prevenção & controle , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/prevenção & controle , Medição de Risco
19.
JAMA ; 322(7): 652-665, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31429903

RESUMO

Importance: Potentially harmful mutations of the breast cancer susceptibility 1 and 2 genes (BRCA1/2) are associated with increased risk for breast, ovarian, fallopian tube, and peritoneal cancer. For women in the United States, breast cancer is the most common cancer after nonmelanoma skin cancer and the second leading cause of cancer death. In the general population, BRCA1/2 mutations occur in an estimated 1 in 300 to 500 women and account for 5% to 10% of breast cancer cases and 15% of ovarian cancer cases. Objective: To update the 2013 US Preventive Services Task Force (USPSTF) recommendation on risk assessment, genetic counseling, and genetic testing for BRCA-related cancer. Evidence Review: The USPSTF reviewed the evidence on risk assessment, genetic counseling, and genetic testing for potentially harmful BRCA1/2 mutations in asymptomatic women who have never been diagnosed with BRCA-related cancer, as well as those with a previous diagnosis of breast, ovarian, tubal, or peritoneal cancer who have completed treatment and are considered cancer free. In addition, the USPSTF reviewed interventions to reduce the risk for breast, ovarian, tubal, or peritoneal cancer in women with potentially harmful BRCA1/2 mutations, including intensive cancer screening, medications, and risk-reducing surgery. Findings: For women whose family or personal history is associated with an increased risk for harmful mutations in the BRCA1/2 genes, or who have an ancestry associated with BRCA1/2 gene mutations, there is adequate evidence that the benefits of risk assessment, genetic counseling, genetic testing, and interventions are moderate. For women whose personal or family history or ancestry is not associated with an increased risk for harmful mutations in the BRCA1/2 genes, there is adequate evidence that the benefits of risk assessment, genetic counseling, genetic testing, and interventions are small to none. Regardless of family or personal history, the USPSTF found adequate evidence that the overall harms of risk assessment, genetic counseling, genetic testing, and interventions are small to moderate. Conclusions and Recommendation: The USPSTF recommends that primary care clinicians assess women with a personal or family history of breast, ovarian, tubal, or peritoneal cancer or who have an ancestry associated with BRCA1/2 gene mutations with an appropriate brief familial risk assessment tool. Women with a positive result on the risk assessment tool should receive genetic counseling and, if indicated after counseling, genetic testing. (B recommendation) The USPSTF recommends against routine risk assessment, genetic counseling, or genetic testing for women whose personal or family history or ancestry is not associated with potentially harmful BRCA1/2 gene mutations. (D recommendation).


Assuntos
Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Aconselhamento Genético , Testes Genéticos , Mutação , Neoplasias Ovarianas/genética , Neoplasias da Mama/prevenção & controle , Neoplasias das Tubas Uterinas/genética , Feminino , Predisposição Genética para Doença , Humanos , Neoplasias Ovarianas/prevenção & controle , Neoplasias Peritoneais/genética , Medição de Risco
20.
Medicine (Baltimore) ; 98(31): e16625, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31374029

RESUMO

Cullin proteins couple with RING-finger proteins, adaptor proteins and substrate recognition receptors to form E3 ubiquitin ligases for recognizing numerous substrates and participating in a variety of cellular processes, especially in genome stability and tumorigenesis. However, the prognostic values of Cullins in breast cancer remain elusive.A "Kaplan-Meier plotter" (KM plotter) online survival analysis tool was used to evaluate the association of individual Cullin members' mRNA expression with overall survival (OS) in breast cancer patients.Our results revealed that elevated mRNA expression of CUL4A and PARC were significantly associated with poor OS for breast cancer patients. While high mRNA expression of CUL2, CUL4B, and CUL5 were correlated with better survival for breast cancers.The associated results suggested that some Cullin members could serve as new predictive prognostic indicators for breast cancer.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Proteínas Culina/biossíntese , RNA Mensageiro/biossíntese , Neoplasias da Mama/patologia , Proteínas de Transporte/biossíntese , Humanos , Estimativa de Kaplan-Meier , Gradação de Tumores
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