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1.
Lancet Oncol ; 21(10): 1296-1308, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32919527

RESUMO

BACKGROUND: Circulating tumour DNA (ctDNA) testing might provide a current assessment of the genomic profile of advanced cancer, without the need to repeat tumour biopsy. We aimed to assess the accuracy of ctDNA testing in advanced breast cancer and the ability of ctDNA testing to select patients for mutation-directed therapy. METHODS: We did an open-label, multicohort, phase 2a, platform trial of ctDNA testing in 18 UK hospitals. Participants were women (aged ≥18 years) with histologically confirmed advanced breast cancer and an Eastern Cooperative Oncology Group performance status 0-2. Patients had completed at least one previous line of treatment for advanced breast cancer or relapsed within 12 months of neoadjuvant or adjuvant chemotherapy. Patients were recruited into four parallel treatment cohorts matched to mutations identified in ctDNA: cohort A comprised patients with ESR1 mutations (treated with intramuscular extended-dose fulvestrant 500 mg); cohort B comprised patients with HER2 mutations (treated with oral neratinib 240 mg, and if oestrogen receptor-positive with intramuscular standard-dose fulvestrant); cohort C comprised patients with AKT1 mutations and oestrogen receptor-positive cancer (treated with oral capivasertib 400 mg plus intramuscular standard-dose fulvestrant); and cohort D comprised patients with AKT1 mutations and oestrogen receptor-negative cancer or PTEN mutation (treated with oral capivasertib 480 mg). Each cohort had a primary endpoint of confirmed objective response rate. For cohort A, 13 or more responses among 78 evaluable patients were required to infer activity and three or more among 16 were required for cohorts B, C, and D. Recruitment to all cohorts is complete and long-term follow-up is ongoing. This trial is registered with ClinicalTrials.gov, NCT03182634; the European Clinical Trials database, EudraCT2015-003735-36; and the ISRCTN registry, ISRCTN16945804. FINDINGS: Between Dec 21, 2016, and April 26, 2019, 1051 patients registered for the study, with ctDNA results available for 1034 patients. Agreement between ctDNA digital PCR and targeted sequencing was 96-99% (n=800, kappa 0·89-0·93). Sensitivity of digital PCR ctDNA testing for mutations identified in tissue sequencing was 93% (95% CI 83-98) overall and 98% (87-100) with contemporaneous biopsies. In all cohorts, combined median follow-up was 14·4 months (IQR 7·0-23·7). Cohorts B and C met or exceeded the target number of responses, with five (25% [95% CI 9-49]) of 20 patients in cohort B and four (22% [6-48]) of 18 patients in cohort C having a response. Cohorts A and D did not reach the target number of responses, with six (8% [95% CI 3-17]) of 74 in cohort A and two (11% [1-33]) of 19 patients in cohort D having a response. The most common grade 3-4 adverse events were raised gamma-glutamyltransferase (13 [16%] of 80 patients; cohort A); diarrhoea (four [25%] of 20; cohort B); fatigue (four [22%] of 18; cohort C); and rash (five [26%] of 19; cohort D). 17 serious adverse reactions occurred in 11 patients, and there was one treatment-related death caused by grade 4 dyspnoea (in cohort C). INTERPRETATION: ctDNA testing offers accurate, rapid genotyping that enables the selection of mutation-directed therapies for patients with breast cancer, with sufficient clinical validity for adoption into routine clinical practice. Our results demonstrate clinically relevant activity of targeted therapies against rare HER2 and AKT1 mutations, confirming these mutations could be targetable for breast cancer treatment. FUNDING: Cancer Research UK, AstraZeneca, and Puma Biotechnology.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , DNA Tumoral Circulante/sangue , Terapia de Alvo Molecular , Adulto , Idoso , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/genética , Feminino , Fulvestranto/uso terapêutico , Genótipo , Humanos , Pessoa de Meia-Idade , Mutação , PTEN Fosfo-Hidrolase/genética , Estudos Prospectivos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Quinolinas/uso terapêutico , Receptor ErbB-2/genética , Receptores Estrogênicos/antagonistas & inibidores , Receptores Estrogênicos/genética , Receptores Estrogênicos/metabolismo , Resultado do Tratamento
2.
Medicine (Baltimore) ; 99(38): e22037, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32957322

RESUMO

To investigate the relationship between serum lipoprotein (a) (LP(a)) levels and breast cancer as well as the clinicopathologic characteristics of breast cancer in a Han Chinese population.This study included 314 breast cancer patients, 51 patients with benign breast tumors, and 185 healthy control subjects. All study subjects were Han Chinese with similar socio-economic backgrounds, who were local residents of Zhoushan, Zhejiang, China or who had lived in Zhoushan for a long period of time. Serum concentrations of LP(a) were determined using a latex-enhanced immunoturbidimetric assay. Clinicopathological characteristics of patients were retrieved from medical records, which included the histopathological type, grade, stage, and molecular subtype of the disease, the expression of estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki67, and the level of reproductive hormones. Correlations between 2 groups were evaluated using the Spearman correlation analysis. Associations among ≥3 groups were interpreted using the Kruskal-Wallis H test or the logistic regression test.Elevated serum LP(a) levels were detected in breast cancer patients compared with healthy control subjects, but no significant differences in LP(a) were detected between breast cancer and benign tumor or between benign tumor and healthy control. In breast cancer patients, serum LP(a) levels were inversely associated with HER2 expression, but they were not significantly correlated with any other clinicopathologic characteristics of breast cancer evaluated in this study.Elevated serum LP(a) levels were associated with breast cancer in a Han Chinese population.


Assuntos
Neoplasias da Mama/etnologia , Grupos Étnicos/estatística & dados numéricos , Hiperlipoproteinemias/etnologia , Lipoproteína(a)/sangue , China/epidemiologia , Feminino , Humanos , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Índice de Gravidade de Doença
3.
Anticancer Res ; 40(9): 4829-4841, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878771

RESUMO

Most breast cancers express the estrogen receptor (ER) receptor and are negative for the human epidermal growth factor receptor 2 (HER2) receptor. ER+/HER2- cancers are treated with hormone-based therapies in the adjuvant setting and derive significant survival benefit from these therapies in the metastatic setting. However, hormone resistance develops in most metastatic patients. An increased understanding of the biology of ER+/HER2- breast cancers has led to the development of new therapies for this disease including CDK4/6 inhibitors and PI3K inhibitors. Several other neoplastic processes are targeted by novel drugs in clinical development, addressing cancer vulnerabilities. These include newer ways to block the ER and targeting the HER2 receptors in ER+/HER2- cancers expressing HER2 in low levels not qualifying for clinical positivity. In addition, promising therapeutic options include targeting other surface receptors or their downstream pathways, as well as targeting the apoptotic machinery and boosting the immune response which is initially insufficient in these cancers. A selection of new drugs in advanced development for ER+/HER2- breast cancer will be discussed in this review.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Mutação , Fosfatidilinositol 3-Quinases/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Receptores Estrogênicos/antagonistas & inibidores , Receptores Estrogênicos/genética , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/efeitos dos fármacos
4.
Medicine (Baltimore) ; 99(30): e21344, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32791733

RESUMO

RATIONALE: Locoregional recurrence of breast cancer is a challenging issue for clinicians. Treatment options for unresectable recurrent estrogen receptor positive (ER+) breast cancer in previously irradiated area are limited. Some studies showed concomitant fulvestrant with radiation therapy might increase radiosensitivity compared with radiation alone in vitro, no in vivo reports yet. PATIENT CONCERN: Here, we present a case report and make a narrative review of concomitant fulvestrant with radiation therapy for unresectable locoregional recurrent ER+ breast cancer. The patient was treated with modified radical mastectomy in 2015, adjuvant chemotherapy, radiotherapy, followed by exemestane until November 2018, relapsed in internal mammary lymph nodes with sternum involved. DIAGNOSIS: The final diagnosis was breast cancer internal mammary lymph nodes metastasis with sternum involved. INTERVENTIONS: After diagnosis was made, concurrent fulvestrant with reirradiation as a palliative treatment were proposed under multiple disciplinary team. OUTCOMES: There was a good clinical response, enabling curative chance with radiation therapy to a total dose of 60 Gy. Computed tomography scan revealed no evidence of residual tumor. LESSONS: As far as we know, this is the first report concerning concomitant fulvestrant with reirradiation for unresectable locoregional recurrent ER+ breast cancer. Since no severe adverse events were observed, this strategy could be a suitable "loco-regional rescue therapy" to further reduce tumor progression or even reach a curative effect. Studies of this treatment strategy in randomized clinical trials are warranted to further assess its safety and effectiveness.


Assuntos
Neoplasias da Mama/terapia , Antagonistas do Receptor de Estrogênio/uso terapêutico , Fulvestranto/uso terapêutico , Reirradiação/métodos , Androstadienos/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Quimioterapia Adjuvante/métodos , Terapia Combinada , Feminino , Humanos , Metástase Linfática/diagnóstico por imagem , Metástase Linfática/patologia , Mastectomia Radical Modificada/métodos , Pessoa de Meia-Idade , Medicina Narrativa/métodos , Recidiva Local de Neoplasia/cirurgia , Receptores Estrogênicos/metabolismo
5.
J Exp Clin Cancer Res ; 39(1): 171, 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32854728

RESUMO

The Covid-19 pandemic has challenged hard the national health systems worldwide. According to the national policy issued in March 2020 in response to the evolving Covid-19 pandemic, several hospitals were re-configured as Covid-19 centers and elective surgery procedures were rescheduled according to the most recent recommendations. In addition, Covid-19 protected cancer hubs were established, including the Regina Elena National Cancer Institute of Rome, Central Italy. At our Institute, the Breast Surgery Department continued working under the sign of a multidisciplinary approach. The number of professional figures involved in case evaluation was reduced to a minimum and interactions took place in the full respect of the required safety measures. Treatments for benign disease, pure prophylactic surgery and elective reconstructive procedures were all postponed and priority was assigned to the histologically-proven malignant breast tumors and highly suspicious lesions. From March 15th though April 30th 2020, we treated a total of 79 patients. This number is fully consistent with the average quantitative standards reached by our Department under ordinary circumstances. Patients were mostly discharged the day after surgery and none was readmitted due to surgery-related late complications. More generally, post-operative complications rates were unexpectedly low, particularly in light of the relatively high number of reconstructive procedures performed in this emergency situation. A strict follow up was performed based on the close contact with the surgical staff by telephone, messaging apps and telemedicine.Patients ascertainment for their Covid-19 status prior to hospital admission and hospital discharge allowed to maintain the "no-Covid-19" status at our Institution. In addition, during the aforementioned time window, none of the care providers developed SARS-CoV-2 infection or disease, as shown by the results of anti-SARS-CoV-2 immunoglobulin M and G profiling. In conclusions, elective breast cancer surgery procedures were successfully performed in a lockdown situation due to a novel viral pandemic. The well-coordinated regional and hospital efforts in terms of medical resource re-allocation and definition of clinical priorities allowed to maintain high quality standards of breast cancer care while ensuring safety to the cancer patients and care providers involved.


Assuntos
Betacoronavirus/isolamento & purificação , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/cirurgia , Carcinoma Lobular/cirurgia , Infecções por Coronavirus/prevenção & controle , Mastectomia/estatística & dados numéricos , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Padrões de Prática Médica/normas , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Neoplasias da Mama/virologia , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/virologia , Carcinoma Lobular/patologia , Carcinoma Lobular/virologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Feminino , Seguimentos , Humanos , Itália/epidemiologia , Pessoa de Meia-Idade , Pneumonia Viral/epidemiologia , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Prognóstico , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo
6.
J Am Coll Surg ; 231(4): 434-447.e2, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32771654

RESUMO

BACKGROUND: During the COVID-19 pandemic, surgical delays have been common for patients with ductal carcinoma in situ (DCIS) and early-stage estrogen receptor-positive (ER+) breast cancer, often in favor of neoadjuvant endocrine therapy (NET). To understand possible ramifications of these delays, we examined the association between time to operation and pathologic staging and overall survival (OS). STUDY DESIGN: Patients with DCIS or ER+ cT1-2N0 breast cancer treated from 2010 through 2016 were identified in the National Cancer Database. Time to operation was recorded. Factors associated with pathologic upstaging were examined using logistic regression analyses. Cox proportional hazard models were used to analyze OS. Analyses were stratified by disease stage and initial treatment strategy. RESULTS: There were 378,839 patients identified. Among those undergoing primary surgical procedure, time to operation was within 120 days in > 98% in all groups. Among cT1-2N0 patients selected for NET, operations were performed within 120 days in 59.6% of cT1N0 and 30.9% of cT2N0 patients. Increased time to operation was associated with increased odds of pathologic upstaging in DCIS patients (ER+: 60 to 120 days: odds ratio 1.15; 95% CI, 1.08 to 1.22; more than 120 days: odds ratio 1.44; 95% CI, 1.24 to 1.68; ER-: 60 to 120 days: NS; more than 120 days: odds ratio 1.36; 95% CI, 1.01 to 1.82; 60 days or less: reference), but not in patients with invasive cancer, irrespective of initial treatment strategy. No difference in OS was seen by time to operation in DCIS or NET patients. CONCLUSIONS: Increased time to operation was associated with a small increase in pathologic upstaging in DCIS patients, but did not impact OS. In patients with cT1-2N0 disease, NET use did not impact stage or OS, supporting the safety of delay strategies in ER+ breast cancer patients during the pandemic.


Assuntos
Betacoronavirus , Neoplasias da Mama/diagnóstico , Carcinoma Ductal de Mama/diagnóstico , Infecções por Coronavirus/epidemiologia , Mastectomia/métodos , Estadiamento de Neoplasias , Pneumonia Viral/epidemiologia , Receptores Estrogênicos/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/epidemiologia , Carcinoma Ductal de Mama/cirurgia , Comorbidade , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Pandemias , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida/tendências , Fatores de Tempo , Tempo para o Tratamento , Estados Unidos/epidemiologia , Adulto Jovem
7.
Med Hypotheses ; 143: 110091, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32663742

RESUMO

Breast cancer is the most common cancer in women and is the second most common cause of death in women. Estrogen plays an important role in breast tumor etiopathogenesis. Tamoxifen and other anti-estrogen drugs are used in breast cancer patients who have a positive estrogen receptor (ER). While angiotensin II plays a key role in breast cancer etiology and causes tamoxifen resistance, angiotensin 1-7 has been reported to may reduce the spread and invasion of breast cancer. During the COVID-19 infection, the virus blocks ACE2, and angiotensin 1-7 production discontinued. Angiotensin III production may increase as angiotensin II destruction is reduced. Thus, aminopeptidase upregulation may occur. Increased aminopeptidase may develop resistance to chemotherapy in breast cancer patients receiving chemotherapy. Estrogen can have a protective effect against COVID-19. Estrogen increase causes ER-α upregulation in T lymphocytes. Thus, estrogen increases the release of interferon I and III from T lymphocytes. Increasing interferon I and III alleviates COVID-19 infection. Tamoxifen treatment causes down-regulation, mutation, or loss in estrogen receptors. In the long-term use of tamoxifen, its effects on estrogen receptors can be permanent. Thus, since estrogen receptors are damaged or downregulated, estrogen may not act by binding to these receptors. Tamoxifen is a P-glycoprotein inhibitor, independent of its effect on estrogen receptors. It suppresses T cell functions and interferon release. We think tamoxifen may increase the COVID-19 risk due to its antiestrogen and P-glycoprotein inhibitory effects.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Infecções por Coronavirus/complicações , Resistencia a Medicamentos Antineoplásicos , Pneumonia Viral/complicações , Tamoxifeno/administração & dosagem , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Betacoronavirus , Neoplasias da Mama/complicações , Suscetibilidade a Doenças , Antagonistas de Estrogênios/administração & dosagem , Feminino , Humanos , Interferons , Pandemias , Receptor Tipo 2 de Angiotensina/metabolismo , Receptores Estrogênicos/metabolismo , Risco
8.
Proc Natl Acad Sci U S A ; 117(32): 19566-19577, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32719118

RESUMO

The ventromedial hypothalamus (VMH) plays chief roles regulating energy and glucose homeostasis and is sexually dimorphic. We discovered that expression of metabotropic glutamate receptor subtype 5 (mGluR5) in the VMH is regulated by caloric status in normal mice and reduced in brain-derived neurotrophic factor (BDNF) mutants, which are severely obese and have diminished glucose balance control. These findings led us to investigate whether mGluR5 might act downstream of BDNF to critically regulate VMH neuronal activity and metabolic function. We found that mGluR5 depletion in VMH SF1 neurons did not affect energy balance regulation. However, it significantly impaired insulin sensitivity, glycemic control, lipid metabolism, and sympathetic output in females but not in males. These sex-specific deficits are linked to reductions in intrinsic excitability and firing rate of SF1 neurons. Abnormal excitatory and inhibitory synapse assembly and elevated expression of the GABAergic synthetic enzyme GAD67 also cooperate to decrease and potentiate the synaptic excitatory and inhibitory tone onto mutant SF1 neurons, respectively. Notably, these alterations arise from disrupted functional interactions of mGluR5 with estrogen receptors that switch the normally positive effects of estrogen on SF1 neuronal activity and glucose balance control to paradoxical and detrimental. The collective data inform an essential central mechanism regulating metabolic function in females and underlying the protective effects of estrogen against metabolic disease.


Assuntos
Glicemia/metabolismo , Estrogênios/metabolismo , Receptor de Glutamato Metabotrópico 5/metabolismo , Núcleo Hipotalâmico Ventromedial/fisiologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Metabolismo Energético , Feminino , Glutamato Descarboxilase/metabolismo , Homeostase , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Mutantes , Rede Nervosa , Inibição Neural , Neurônios/metabolismo , Neurônios/fisiologia , Receptor de Glutamato Metabotrópico 5/genética , Receptores Estrogênicos/metabolismo , Fatores Sexuais , Transdução de Sinais , Fator Esteroidogênico 1/metabolismo , Sistema Nervoso Simpático/metabolismo , Transmissão Sináptica , Núcleo Hipotalâmico Ventromedial/citologia , Núcleo Hipotalâmico Ventromedial/metabolismo
10.
Anticancer Res ; 40(8): 4529-4535, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727783

RESUMO

BACKGROUND/AIM: Although ginseng seed oil (GSO) appears to have various roles in the body, its anti-cancer effect has not been investigated. Tamoxifen is widely used to treat estrogen receptor-positive (ER+) breast cancer but shows adverse effects with drug resistance. This study investigated the effect of GSO in ER+ breast cancer cell growth. MATERIALS AND METHODS: Cell viability assays, western blots and Annexin V staining were conducted to examine cell viability and apoptosis. The synergistic effect of tamoxifen in combination with GSO or oleic acid (OA) was determined. RESULTS: GSO and OA caused apoptosis of MCF-7 ER+ breast cancer cells and had synergistic effects with tamoxifen in inhibiting tamoxifen-resistant MCF-7 (MCF-7TAMR) ER+ breast cancer cell growth. CONCLUSION: GSO may block ER+ breast cancer recurrence in combination with tamoxifen.


Assuntos
Neoplasias da Mama/metabolismo , Ácido Oleico/farmacologia , Panax/química , Óleos Vegetais/farmacologia , Receptores Estrogênicos/metabolismo , Tamoxifeno/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Humanos , Células MCF-7 , Óleos Vegetais/química , Sementes/química
11.
Medicine (Baltimore) ; 99(27): e20808, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629666

RESUMO

RATIONALE: Palbociclib (PAL) is a first-in-class selective inhibitor of the cyclin-dependent kinases 4 (CDK4) and CDK6 and is indicated for the treatment of hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) in combination with fulvestrant (FUL) in postmenopausal women. Antrodia cinnamomea (AC), a well-known Chinese folk medicine in Taiwan, possesses numerous biological capabilities, most notably an anti-tumor effect. However, the clinical use of AC as complementary medicine combined with adjuvant therapy is unexplored. In this case report, we evaluated AC combined with PAL plus FUL to reduce the tumor burden in an MBC patient. PATIENT CONCERNS: A Slovenian woman diagnosed with relapsed bone metastases of breast cancer (BC) was unable to undergo surgery and refused radiation therapy due to fear of side effects; she also feared the side effects of adjuvants. However, she was eager to live with a high quality of life. DIAGNOSIS: Stage IV, HR-positive/HER2-negative BC with relapse of bone metastases. INTERVENTIONS: After diagnosis of relapse of bone metastases, she received adjuvant with PAL plus FUL. Additionally, she chose to take AC orally (10 g/d). OUTCOMES: The pain was mostly relieved, and the side effects of adjuvant therapy reduced. Magnetic resonance imaging revealed reduction of tumor size at the fifth month of adjuvant therapy plus AC. After 14 months of adjuvant therapy plus AC, the tumors at the thoracic vertebrae T1 and T3 were found to have shrunk from 35.2 and 12.0 mm to 28.1 and 9.9 mm, respectively. Remarkably, no further metastases were observed. LESSONS: According to the circulating tumor cells (CTCs) test data, AC had better anti-tumor efficacy on active tumor cells than PAL plus FUL. Thus, AC could be an effective complementary medicine for adjuvant therapy in patients with HR-positive/HER2-negative MBC. Interestingly, continued elevation of carcinoma antigen 15-3 and lactate dehydrogenase levels but decreasing levels of alkaline phosphatase were observed, which may be indicative of the potent efficacy of treatment resulting in massive tumor cell death. The CTCs test may be a sensitive approach to monitor the progression of BC and subsequently evaluate the efficiency of therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antrodia , Neoplasias Ósseas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Feminino , Fulvestranto/uso terapêutico , Humanos , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Piperazinas/uso terapêutico , Piridinas/uso terapêutico , Qualidade de Vida , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo
12.
Life Sci ; 257: 118078, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32663577

RESUMO

This study aimed to evaluate the modulatory role of sex-related hormone estradiol on cancer stem cells with the origin of colorectal adenocarcinoma in vitro. Cancer stem cells were incubated with 100 nM estradiol for 48 h. The cell survival rate was analyzed using the MTT assay. Immunocytochemistry staining of Ki-67 and Inhibin and Apoptosis PCR array were done to measure proliferation/apoptosis. Cell migration was monitored via the Transwell Migration assay. The expression of exosome biogenesis genes was measured using a real-time PCR assay. The fatty acid profile was monitored using gas chromatography. The level of FAK, SQSTM1, ER, and SIRT1 was examined using Western blotting. Cancer stem-endothelial cell interaction was investigated using Surface Plasmon Resonance assay. Data showed no significant differences in cancer stem cell viability and proliferation between control and estradiol-treated groups (p>0.05). PCR array highlighted the up-regulation of both pro- and anti-apoptosis effectors in the treatment group compared to the control cells (p<0.05). Cell migration capacity was increased after treatment with estradiol (p<0.001). Both exocytosis and exosome biogenesis were decreased in cancer stem cells exposed to estradiol (p<0.05). Data showed the reduction of palmitic acid, and increase of Palmitoleic and Linolenic acids in estradiol-treated cells. Estrogen induced estrogen receptor, SQSTM1 proteins and decreased SIRT1 factor after 48 h. Surface Plasmon Resonance revealed the suppression of cancer stem-endothelial cell interaction and affinity. Estradiol could change the migration, juxtacrine and paracrine activities of cancer stem cells, showing the importance of sex-related hormones in the dynamic of cancer development.


Assuntos
Neoplasias Colorretais/metabolismo , Células Endoteliais/metabolismo , Estradiol/metabolismo , Células-Tronco Neoplásicas/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Estradiol/farmacologia , Células HT29 , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Receptores Estrogênicos/metabolismo
13.
Anticancer Res ; 40(6): 3097-3108, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487604

RESUMO

BACKGROUND/AIM: C-C motif chemokine ligand 18 (CCL18) is overexpressed in the microenvironment of tumors, promotes invasion and metastasis and is thus important for the therapeutic outcome of many tumor entities. The Gs-coupled seven-transmembrane receptor GPR30 is known as both a CCL18 and an estrogen receptor; its activation by estradiol leads to a transactivation of membrane-tethered pro-heparin-binding EGF-like growth factor and the MAPK/ERK pathway. We examined whether this signaling pathway remains the same under CCL18 stimulation, as opposed to estradiol stimulation. MATERIALS AND METHODS: We investigated the effects of CCL18 on the lung cancer cell line A549, that show low GPR30 expression and the breast cancer cell lines MCF-7, that has high GPR30 expression and MDA-MB-231. These cells were stimulated in different media with CCL18 and then analyzed by qPCR, In-Cell Western®, western blot and ELISA. RESULTS: Many similarities on the effect of CCL18 on the already known estradiol-activated signaling pathway via the G protein-coupled estrogen receptor GPR30 were identified. GPR30 is involved in the expression of matrix metalloproteinases (MMPs), which may play a role in the transactivation of ERK-1/-2 via the cleavage of membrane-bound HB-EGF, via Src-related tyrosine kinases and Gßγ-subunits. With increasing CCL18 concentration, the expression of MMP7 decreased in A549 cells. With decreasing estrogen content of the medium, there was an increasing effect of CCL18 on the inhibition of the relative expression of MMP7. Inhibition of GPR30 with G15 also resulted in a decrease in the relative expression of MMP7, irrespective of the subsequent stimulation with CCL18. This is a rather unexpected result, because the estrogen estradiol and CCL18 both activate GPR30. MCF-7 cells which express more GPR30 did not show any dependence of the relative MMP7 expression on CCL18 except in estrogen-free FCS medium. CCL18 induced an increased relative ERK activation in In-Cell western (ICW) at A549 cells. Stimulation with CCL18 caused decreased ERK activation with simultaneous inhibition of adenylate cyclase in MCF-7. However, stimulation with CCL18 and simultaneous inhibition of cyclooxygenase in MCF-7 resulted in increased ERK activation. In A549, stimulation with CCL18 and co-incubation with dbcAMP resulted in decreased ERK activation in both ICW and Western blot. CONCLUSION: In summary, the Gs-coupled receptor GPR30 plays an important role in the signaling pathway of CCL18. CCL18 and estradiol may not lead to the same signaling pathway after activating GPR30.


Assuntos
Quimiocinas CC/metabolismo , Estradiol/metabolismo , Metaloproteinase 7 da Matriz/metabolismo , Receptores Estrogênicos/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Células A549 , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Quimiocinas CC/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Células MCF-7 , Metaloproteinase 7 da Matriz/biossíntese , Metaloproteinase 7 da Matriz/genética , Fosforilação , RNA Longo não Codificante/biossíntese , RNA Longo não Codificante/genética , Receptores Estrogênicos/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Transdução de Sinais
14.
Chemosphere ; 258: 127304, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32559490

RESUMO

Humans are exposed to numerous endocrine disruptors on a daily basis, which may interfere with endogenous estrogens, with Di-(2-ethylhexyl) phthalate (DEHP) being one of the most employed. The anterior pituitary gland is a target of 17ß-estradiol (E2) through the specific estrogen receptors (ERs) α and ß, whose expression levels fluctuate in the gland under different contexts, and the ERα/ß index is responsible for the final E2 effect. The aim of the present study was to evaluate in vivo and in vitro the DEHP effects on ERα and ß expression in the pituitary cell population, and also its impact on lactotroph and somatotroph cell growth. Our results revealed that perinatal exposure to DEHP altered the ERα and ß expression pattern in pituitary glands from prepubertal and adult female rats and increased the percentage of lactotroph cells in adulthood. In the in vitro system, DEHP down-regulated ERα and ß expression, and as a result increased the ERα/ß ratio and decreased the percentages of lactotrophs and somatotrophs expressing ERα and ß. In addition, DEHP increased the S + G2M phases, Ki67 index and cyclin D1 in vitro, leading to a rise in the lactotroph and somatotroph cell populations. These results showed that DEHP modified the pituitary ERα and ß expression in lactotrophs and somatotrophs from female rats and had an impact on the pituitary cell growth. These changes in ER expression may be a mechanism underlying DEHP exposure in the pituitary gland, leading to cell growth deregulation.


Assuntos
Dietilexilftalato/toxicidade , Ácidos Ftálicos/toxicidade , Receptores Estrogênicos/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Dietilexilftalato/metabolismo , Disruptores Endócrinos/metabolismo , Estradiol/metabolismo , Receptor alfa de Estrogênio/metabolismo , Estrogênios/farmacologia , Feminino , Lactotrofos/efeitos dos fármacos , Lactotrofos/metabolismo , Hipófise/efeitos dos fármacos , Ratos
15.
Environ Toxicol ; 35(11): 1179-1193, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32530119

RESUMO

Tamoxifen was widely applied in the therapy of estrogen receptor (ER)-positive breast cancer. With the purpose of determining the potential impacts of quercetin on its effectiveness, MCF-7 cells were selected as the in vitro model and several cellular biological behaviors (ie, cell proliferation, migration, invasion, cycle, apoptosis, and oxidative stress) were investigated. As results, quercetin showed contrasting dose-response to cellular behaviors dependent on the ROS-regulated p53 signaling pathways. In detail, quercetin promoted cell proliferation and inhibited cell apoptosis at low concentrations, whereas high-concentration resulted in apoptosis induction. Moreover, quercetin at a low concentration significantly inhibited tamoxifen-induced antiproliferation in MCF-7 cells, whereas high concentrations enhanced cell apoptosis in a synergetic manner. The real-time quantitative polymerase chain reaction analysis further implied that quercetin exerted its dual roles in tamoxifen-induced antiproliferative effects by regulated the gene expression involved in cell metastasis, cycle, and apoptosis through the ER pathways. Our present study provides a considerable support to the combination of quercetin and tamoxifen on human ER-positive breast carcinoma management.


Assuntos
Antioxidantes/farmacologia , Neoplasias da Mama/tratamento farmacológico , Quercetina/farmacologia , Tamoxifeno/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Proliferação de Células/efeitos dos fármacos , Estrogênios , Feminino , Humanos , Células MCF-7 , Receptores Estrogênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos
16.
Proc Natl Acad Sci U S A ; 117(26): 15047-15054, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32532922

RESUMO

Tamoxifen, a widely used modulator of the estrogen receptor (ER), targets ER-positive breast cancer preferentially. We used a powerful validation-based insertion mutagenesis method to find that expression of a dominant-negative, truncated form of the histone deacetylase ZIP led to resistance to tamoxifen. Consistently, increased expression of full-length ZIP gives the opposite phenotype, inhibiting the expression of genes whose products mediate resistance. An important example is JAK2 By binding to two specific sequences in the promoter, ZIP suppresses JAK2 expression. Increased expression and activation of JAK2 when ZIP is inhibited lead to increased STAT3 phosphorylation and increased resistance to tamoxifen, both in cell culture experiments and in a mouse xenograft model. Furthermore, data from human tumors are consistent with the conclusion that decreased expression of ZIP leads to resistance to tamoxifen in ER-positive breast cancer.


Assuntos
Neoplasias da Mama/enzimologia , Proteínas Quinases Associadas com Morte Celular/metabolismo , Resistencia a Medicamentos Antineoplásicos , Janus Quinase 2/metabolismo , Fator de Transcrição STAT3/metabolismo , Tamoxifeno/farmacologia , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proteínas Quinases Associadas com Morte Celular/genética , Feminino , Humanos , Janus Quinase 2/genética , Camundongos , Camundongos SCID , Receptores Estrogênicos/genética , Receptores Estrogênicos/metabolismo , Fator de Transcrição STAT3/genética
17.
Mol Cell ; 78(5): 876-889.e6, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32502422

RESUMO

Many microRNAs (miRNAs) are generated from primary transcripts containing multiple clustered stem-loop structures that are thought to be recognized and cleaved by the Microprocessor complex as independent units. Here, we uncover an unexpected mode of processing of the bicistronic miR-15a-16-1 cluster. We find that the primary miR-15a stem-loop is not processed on its own but that the presence of the neighboring primary miR-16-1 stem-loop on the same transcript can compensate for this deficiency in cis. Using a CRISPR/Cas9 screen, we identify SAFB2 (scaffold attachment factor B2) as an essential co-factor in this miR-16-1-assisted pri-miR-15 cleavage and describe SAFB2 as an accessory protein of the Microprocessor. Notably, SAFB2-mediated cleavage expands to other clustered pri-miRNAs, indicating a general mechanism. Together, our study reveals an unrecognized function of SAFB2 in miRNA processing and suggests a scenario in which SAFB2 enables the binding and processing of suboptimal Microprocessor substrates in clustered primary miRNA transcripts.


Assuntos
Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , MicroRNAs/metabolismo , Proteínas Associadas à Matriz Nuclear/metabolismo , Receptores Estrogênicos/metabolismo , Animais , Linhagem Celular , Núcleo Celular/metabolismo , Células HEK293 , Humanos , Sequências Repetidas Invertidas/genética , Sequências Repetidas Invertidas/fisiologia , Proteínas de Ligação à Região de Interação com a Matriz/genética , Camundongos , MicroRNAs/genética , Proteínas Associadas à Matriz Nuclear/genética , Conformação de Ácido Nucleico , Processamento Pós-Transcricional do RNA/genética , Proteínas de Ligação a RNA/metabolismo , Receptores Estrogênicos/genética
18.
Chemosphere ; 256: 127159, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32559890

RESUMO

Although epidemiological and animal studies suggest a possible correlation between bisphenol A (BPA) exposure and atherosclerosis, very few in vitro mechanistic and functional studies regarding the effect of BPA on vascular cells have been conducted. Here, we applied a "real-life" exposure scenario by continuously exposing human endothelial cell (EC) line EA.hy926 to environmentally relevant concentrations of BPA (10-9, 10-8, and 10-7 M) during 14 weeks. We also exposed EA.hy926 cells to higher concentrations of BPA (10-7, 10-6, and 10-5 M) for up to 48 h to gain mechanistic insight into the BPA's action in ECs. Chronic exposure to BPA produced some unexpected effects in EA.hy926 cells including a transient decrease in the adhesion of monocytes to the EC monolayer and decrease in the expression of cellular adhesion molecules, improvement in endothelial barrier function and elevated expression of tight junction proteins occludin and zonula occludens-1 (ZO-1), increased adhesion of ECs, and increased nitric oxide (NO) production. Some of these effects, such as diminished adhesion of monocytes to the EC monolayer and elevated NO production have also been replicated during acute exposure experiments. Using Western blotting and specific pharmacological inhibitors in the acute study, we have shown that direct BPA's action in EA.hy926 cells involves activation of estrogen receptor (ER), phosphorylation of protein kinase B (PKB/Akt) and endothelial nitric oxide synthase (eNOS)-mediated production of NO. Collectively, these data indicate that BPA induces functional and molecular changes in EA.hy926 cells associated with the promotion of endothelial integrity through activation of the ER/Akt/eNOS pathway.


Assuntos
Compostos Benzidrílicos/toxicidade , Poluentes Ambientais/toxicidade , Fenóis/toxicidade , Linhagem Celular , Células Endoteliais/metabolismo , Humanos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Estrogênicos/metabolismo , Testes de Toxicidade
19.
Life Sci ; 256: 117983, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32565252

RESUMO

Estrogen receptor (ER) positive accounts for a large proportion of breast cancer. Although there are many targeted therapeutic drugs, the emergence of drug resistance urgently requires the development of new drugs. Arctigenin (Arc), a lignan found in certain plants of the Asteraceae, has the effect on inhibiting breast cancer, but its molecular mechanism has not been clear. AIMS: To this end, the current study focuses on understanding the mechanism of Arc on ER-positive breast cancer cells. MAIN METHODS: Colony formation experiments and sulforhodamine B methods were used to determine the growth-inhibitory effect of Arc. The cell cycle and apoptosis were analyzed by flow cytometry. Alterations of signaling proteins were measured by Western blotting. Protein degradation was determined by comparing protein half-lives and inhibiting proteasome. KEY FINDINGS: The experimental results show that Arc did not induce apoptosis in ER-positive breast cancer cell, rather caused G1 cycle arrest by decreasing cyclin D1 levels without effect on altering CDK4/6 levels. Moreover, we have demonstrated that Arc decreases cyclin D1 levels through prompting Akt/GSK3ß-mediated degradation. SIGNIFICANCE: These findings warrant the potential of Arc as a candidate treatment for ER-positive breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Pontos de Checagem do Ciclo Celular/fisiologia , Ciclina D1/metabolismo , Furanos/farmacologia , Quinase 3 da Glicogênio Sintase/metabolismo , Lignanas/farmacologia , Receptores Estrogênicos/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Relação Dose-Resposta a Droga , Feminino , Furanos/uso terapêutico , Humanos , Lignanas/uso terapêutico , Células MCF-7 , Proteólise/efeitos dos fármacos
20.
PLoS One ; 15(6): e0233571, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497134

RESUMO

PURPOSE: This meta-analysis aimed to assess the efficacy and safety of cyclin-dependent kinase (CDK) 4/6 inhibitors plus endocrine therapy (ET) in hormonal receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). METHODS: We searched PubMed, Embase, Cochrane, ClinicalTrials.gov., ASCO, ESMO and AACR databases from inception to October 10, 2019 for randomized controlled trials (RCTs) that compared CDK 4/6 inhibitors plus ET to single-agent ET with no treatment-line restriction. The main outcomes analyzed were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), and adverse events (AEs). RESULTS: Of 938 identified studies, 9 RCTs with 5043 women were eligible and included. Compared with ET alone, CDK 4/6 inhibitors and ET combination improved in PFS (hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.50-0.59, p< 0.00001) and OS (HR 0.77, 95% CI 0.69-0.85, p< 0.00001), regardless of ET strategies (HR 0.54, 95% CI 0.50-0.59 in PFS; HR 0.77, 95% CI 0.69-0.85 in OS), treatment line of advanced disease (HR 0.52, 95% CI 0.46-0.59 in PFS; HR 0.75, 95% CI 0.66-0.85 in OS) and menopausal status (HR 0.54, 95% CI 0.50-0.58 in PFS; HR 0.76, 95% CI 0.68-0.84 in OS). Higher risk of grade 3/4 AEs (RR 2.66, 95% CI 2.44-2.90, p < 0.00001) were observed in the combination group than in the ET group. CONCLUSIONS: Combination therapy with CDK 4/6 inhibitors and ET prolongs survival in HR+/ HER2- ABC. This combination is a better therapeutic strategy than endocrine monotherapy in HR+/HER2- ABC, regardless of treatment line, menopausal status and other individual characteristics.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos
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