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1.
Ugeskr Laeger ; 183(39)2021 Sep 27.
Artigo em Dinamarquês | MEDLINE | ID: mdl-34596511

RESUMO

About half of all Danish cancer patients are 70 years or older at diagnosis. The incidence is expected to increase further over the coming years because of an increasing longevity. Therefore, this review recommends that the Danish health care system develops and implement models to ensure optimal care for older adults with cancer. We are still in need of knowledge about the optimal treatment, rehabilitation, palliation and care for older adults with cancer. We encourage the Danish health authorities to formulate a national strategy for this area.

3.
Nat Commun ; 12(1): 5112, 2021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433817

RESUMO

CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy have shown impressive efficacy in estrogen receptor-positive advanced breast cancer. However, most patients will eventually experience disease progression on this combination, underscoring the need for effective subsequent treatments or better initial therapies. Here, we show that triple inhibition with fulvestrant, CDK4/6i and AKT inhibitor (AKTi) durably impairs growth of breast cancer cells, prevents progression and reduces metastasis of tumor xenografts resistant to CDK4/6i-fulvestrant combination or fulvestrant alone. Importantly, switching from combined fulvestrant and CDK4/6i upon resistance to dual combination with AKTi and fulvestrant does not prevent tumor progression. Furthermore, triple combination with AKTi significantly inhibits growth of patient-derived xenografts resistant to combined CDK4/6i and fulvestrant. Finally, high phospho-AKT levels in metastasis of breast cancer patients treated with a combination of CDK4/6i and endocrine therapy correlates with shorter progression-free survival. Our findings support the clinical development of ER, CDK4/6 and AKT co-targeting strategies following progression on CDK4/6i and endocrine therapy combination, and in tumors exhibiting high phospho-AKT levels, which are associated with worse clinical outcome.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Fulvestranto/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/metabolismo , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Quimioterapia Combinada , Feminino , Humanos , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas c-akt/genética
4.
Breast Cancer Res ; 23(1): 26, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33602273

RESUMO

BACKGROUND: Resistance to endocrine treatment in metastatic breast cancer is a major clinical challenge. Clinical tools to predict both drug resistance and possible treatment combination approaches to overcome it are lacking. This unmet need is mainly due to the heterogeneity underlying both the mechanisms involved in resistance development and breast cancer itself. METHODS: To study the complexity of the mechanisms involved in the resistance to the selective estrogen receptor degrader (SERD) fulvestrant, we performed comprehensive biomarker analyses using several in vitro models that recapitulate the heterogeneity of developed resistance. We further corroborated our findings in tissue samples from patients treated with fulvestrant. RESULTS: We found that different in vitro models of fulvestrant resistance show variable stability in their phenotypes, which corresponded with distinct genomic alterations. Notably, the studied models presented adaptation at different cell cycle nodes to facilitate progression through the cell cycle and responded differently to CDK inhibitors. Cyclin E2 overexpression was identified as a biomarker of a persistent fulvestrant-resistant phenotype. Comparison of pre- and post-treatment paired tumor biopsies from patients treated with fulvestrant revealed an upregulation of cyclin E2 upon development of resistance. Moreover, overexpression of this cyclin was found to be a prognostic factor determining resistance to fulvestrant and shorter progression-free survival. CONCLUSIONS: These data highlight the complexity of estrogen receptor positive breast cancer and suggest that the development of diverse resistance mechanisms dictate levels of ER independence and potentially cross-resistance to CDK inhibitors.

5.
Stem Cells ; 39(2): 133-143, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33211379

RESUMO

Since the discovery of breast cancer stem cells (CSCs), a significant effort has been made to identify and characterize these cells. It is a generally believe that CSCs play an important role in cancer initiation, therapy resistance, and progression of triple-negative breast cancer (TNBC), an aggressive breast cancer subtype with poor prognosis. Thus, therapies targeting these cells would be a valuable addition to standard treatments that primarily target more differentiated, rapidly dividing TNBC cells. Although several cell surface and intracellular proteins have been described as biomarkers for CSCs, none of these are specific to this population of cells. Recent research is moving toward cellular signaling pathways as targets and biomarkers for CSCs. The WNT pathway, the nuclear factor-kappa B (NF-κB) pathway, and the cholesterol biosynthesis pathway have recently been identified to play a key role in proliferation, survival, and differentiation of CSCs, including those of breast cancer. In this review, we assess recent findings related to these three pathways in breast CSC, with particular focus on TNBC CSCs, and discuss how targeting these pathways, in combination with current standard of care, might prove effective and improve the prognosis of TNBC patients.

6.
Nat Commun ; 11(1): 5878, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33208750

RESUMO

HER2-targeted therapy has yielded a significant clinical benefit in patients with HER2+ breast cancer, yet disease relapse due to intrinsic or acquired resistance remains a significant challenge in the clinic. Here, we show that the protein phosphatase 2A (PP2A) regulatory subunit PPP2R2B is a crucial determinant of anti-HER2 response. PPP2R2B is downregulated in a substantial subset of HER2+ breast cancers, which correlates with poor clinical outcome and resistance to HER2-targeted therapies. EZH2-mediated histone modification accounts for the PPP2R2B downregulation, resulting in sustained phosphorylation of PP2A targets p70S6K and 4EBP1 which leads to resistance to inhibition by anti-HER2 treatments. Genetic depletion or inhibition of EZH2 by a clinically-available EZH2 inhibitor restores PPP2R2B expression, abolishes the residual phosphorylation of p70S6K and 4EBP1, and resensitizes HER2+ breast cancer cells to anti-HER2 treatments both in vitro and in vivo. Furthermore, the same epigenetic mechanism also contributes to the development of acquired resistance through clonal selection. These findings identify EZH2-dependent PPP2R2B suppression as an epigenetic control of anti-HER2 resistance, potentially providing an opportunity to mitigate anti-HER2 resistance with EZH2 inhibitors.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteína Fosfatase 2/metabolismo , Receptor ErbB-2/metabolismo , Animais , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Feminino , Humanos , Camundongos , Camundongos Nus , Proteínas do Tecido Nervoso/genética , Proteína Fosfatase 2/genética , Quinazolinas/administração & dosagem , Receptor ErbB-2/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo
7.
Cell Rep ; 27(13): 3927-3938.e6, 2019 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-31242424

RESUMO

Tumor eradication may be greatly improved by targeting cancer stem cells (CSCs), as they exhibit resistance to conventional therapy. To gain insight into the unique biology of CSCs, we developed patient-derived xenograft tumors (PDXs) from ER- breast cancers from which we isolated mammospheres that are enriched for CSCs. Comparative global proteomic analysis was performed on patient tumor tissues and corresponding PDXs and mammospheres. Mammospheres exhibited increased expression of proteins associated with de novo cholesterol synthesis. The clinical relevance of increased cholesterol biosynthesis was verified in a large breast cancer cohort showing correlation with shorter relapse-free survival. RNAi and chemical inhibition of the cholesterol biosynthesis pathway reduced mammosphere formation, which could be rescued by a downstream metabolite. Our findings identify the cholesterol biosynthesis pathway as central for CSC propagation and a potential therapeutic target, as well as providing a mechanistic explanation for the therapeutic benefit of statins in breast cancer.


Assuntos
Colesterol/biossíntese , Células-Tronco Neoplásicas/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Células-Tronco Neoplásicas/patologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia
8.
Int J Cancer ; 144(3): 631-640, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30110125

RESUMO

Prognostic and predictive biomarkers of disease and treatment outcome are needed to ensure optimal treatment of patients with triple-negative breast cancer (TNBC). In a mass spectrometry-based global proteomic study of 44 formalin-fixed, paraffin-embedded (FFPE) primary TNBC tumors and 10 corresponding metastases, we found that Cytochrome P450 reductase (CYPOR) expression correlated with patient outcome. The correlation between CYPOR expression and outcome was further evaluated in a Danish cohort of 113 TNBC patients using immunohistochemistry and publicly available gene expression data from two cohorts of TNBC and basal-like breast cancer patients, respectively (N = 249 and N = 580). A significant correlation between high CYPOR gene expression and shorter recurrence-free survival (RFS), but not overall survival, was found in the cohort of 249 TNBC patients (p = 0.018, HR = 1.77, 95% CI 1.1-2.85), and this correlation was recapitulated in a cohort of 580 basal-like breast cancer patients (p = 0.018, HR = 1.4, 95% CI 1.06-1.86). High CYPOR protein expression was also associated with shorter RFS in the cohort of 113 TNBC patients (p = 0.017, HR = 2.73, 95% CI 1.20-6.19), particularly those who were lymph node tumor-negative (p = 0.029, HR = 5.22). Multivariate Cox regression analysis identified CYPOR as an independent prognostic factor for shorter RFS in TNBC patients (p = 0.032, HR = 2.19, 95% CI 1.07-4.47). Together, these data suggest high expression of CYPOR as an independent prognostic biomarker of shorter RFS, which could be used to identify patients who should receive more extensive adjuvant treatment and more aggressive surveillance.


Assuntos
Biomarcadores Tumorais/biossíntese , NADPH-Ferri-Hemoproteína Redutase/biossíntese , Neoplasias de Mama Triplo Negativas/enzimologia , Biomarcadores Tumorais/genética , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Linfonodos/patologia , Metástase Linfática , Pessoa de Meia-Idade , NADPH-Ferri-Hemoproteína Redutase/genética , Recidiva Local de Neoplasia/enzimologia , Recidiva Local de Neoplasia/patologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
9.
Mol Oncol ; 12(6): 925-935, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29689598

RESUMO

Liquid biopsies focusing on the analysis of cell-free circulating tumor DNA (ctDNA) may have important clinical implications for personalized medicine, including early detection of cancer, therapeutic guidance, and monitoring of recurrence. Mutations in the oncogene, PIK3CA, are frequently observed in breast cancer and have been suggested as a predictive biomarker for PI3K-selective inhibitor treatment. In this study, we analyzed the presence of PIK3CA mutations in formalin-fixed, paraffin-embedded, metastatic tissue and corresponding ctDNA from serum of patients with advanced breast cancer using a highly sensitive, optimized droplet digital PCR (ddPCR) assay. We found 83% of patients with PIK3CA mutation in the metastatic tumor tissue also had detectable PIK3CA mutations in serum ctDNA. Patients lacking the PIK3CA mutation in corresponding serum ctDNA all had nonvisceral metastatic disease. Four patients with detectable PIK3CA-mutated ctDNA were followed with an additional serum sample during oncological treatment. In all cases, changes in PIK3CA ctDNA level correlated with treatment response. Our results showed high concordance between detection of PIK3CA mutations in tumor tissue and in corresponding serum ctDNA and suggest that serum samples from patients with advanced breast cancer and ddPCR may be used for PIK3CA mutation status assessment to complement imaging techniques as an early marker of treatment response.


Assuntos
Neoplasias da Mama/sangue , Neoplasias da Mama/genética , DNA Tumoral Circulante/sangue , Classe I de Fosfatidilinositol 3-Quinases/genética , Mutação Puntual/genética , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Análise Mutacional de DNA , Feminino , Humanos , Metástase Neoplásica , Resultado do Tratamento
10.
Stem Cells ; 35(8): 1898-1912, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28600813

RESUMO

A limited number of cancer cells within a tumor are thought to have self-renewing and tumor-initiating capabilities that produce the remaining cancer cells in a heterogeneous tumor mass. Elucidation of central pathways preferentially used by tumor-initiating cells/cancer stem cells (CSCs) may allow their exploitation as potential cancer therapy targets. We used single cell cloning to isolate and characterize four isogenic cell clones from a triple-negative breast cancer cell line; two exhibited mesenchymal-like and two epithelial-like characteristics. Within these pairs, one, but not the other, resulted in tumors in immunodeficient NOD/Shi-scid/IL-2 Rγ null mice and efficiently formed mammospheres. Quantitative proteomics and phosphoproteomics were used to map signaling pathways associated with the tumor-initiating ability. Signaling associated with apoptosis was suppressed in tumor-initiating versus nontumorigenic counterparts with pro-apoptotic proteins, such as Bcl2-associated agonist of cell death (BAD), FAS-associated death domain protein (FADD), and myeloid differentiation primary response protein (MYD88), downregulated in tumor-initiating epithelial-like cells. Functional studies confirmed significantly lower apoptosis in tumor-initiating versus nontumorigenic cells. Moreover, central pathways, including ß-catenin and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-related signaling, exhibited increased activation in the tumor-initiating cells. To evaluate the CSC model as a tool for drug screening, we assessed the effect of separately blocking NF-κB and Wnt/ß-catenin signaling and found markedly reduced mammosphere formation, particularly for tumor-initiating cells. Similar reduction was also observed using patient-derived primary cancer cells. Furthermore, blocking NF-κB signaling in mice transplanted with tumor-initiating cells significantly reduced tumor outgrowth. Our study demonstrates that suppressed apoptosis, activation of pathways associated with cell viability, and CSCs are the major differences between tumor-initiating and nontumorigenic cells independent of their epithelial-like/mesenchymal-like phenotype. These altered pathways may provide targets for future drug development to eliminate CSCs, and the cell model may be a useful tool in such drug screenings. Stem Cells 2017;35:1898-1912.


Assuntos
Avaliação Pré-Clínica de Medicamentos , Modelos Biológicos , Células-Tronco Neoplásicas/patologia , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Animais , Antígenos CD/metabolismo , Apoptose , Biomarcadores Tumorais/metabolismo , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Proliferação de Células , Forma Celular , Sobrevivência Celular , Transição Epitelial-Mesenquimal , Feminino , Humanos , Espectrometria de Massas , Camundongos , Mapas de Interação de Proteínas , Proteômica , Reprodutibilidade dos Testes , Esferoides Celulares/patologia , Via de Sinalização Wnt
11.
Int J Cancer ; 137(9): 2093-103, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25912829

RESUMO

Triple-negative breast cancer (TNBC) represents a heterogeneous subgroup with generally poor outcome and lack of an effective targeted therapy. Prognostic or predictive biomarkers to guide treatment decisions for this group of patients are needed. To evaluate the potential of S100A14 protein as a novel biomarker in TNBC, the protein expression of S100A14 was correlated with clinical outcomes in a Pilot Sample set and a Danish cohort of predominantly TNBC patients. Kaplan-Meier analysis identified a prognostic impact of S100A14 on disease-free survival and overall survival, showing that tumors with high S100A14 protein expression levels were significantly correlated with poor outcome in TNBC patients (p = 0.017; p = 0.038), particularly those in the basal-like subgroup (p = 0.006; p = 0.037). Importantly, TNBC patients with high S100A14 expression, but tumor-negative axillary lymph nodes (N-), had equally poor outcomes as those with tumor-positive axillary lymph nodes (N+), while TNBC/N- patients with low S100A14 expression had a significantly better disease free survival (p = 0.013). Multivariate analysis revealed that S100A14 is an independent prognostic factor for TNBC patients (p = 0.024; p = 0.05). At the cellular level, S100A14 was found to be expressed in epithelial-like, but not in mesenchymal-like, TNBC cells in vitro. S100A14 is an independent prognostic factor in TNBC and a novel potential therapeutic target in TNBC.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Carcinoma Ductal de Mama/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Carcinoma Ductal de Mama/mortalidade , Carcinoma Ductal de Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Projetos Piloto , Prognóstico , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia
12.
Biochem J ; 437(2): 231-41, 2011 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-21539519

RESUMO

ACBP (acyl-CoA-binding protein) is a small primarily cytosolic protein that binds acyl-CoA esters with high specificity and affinity. ACBP has been identified in all eukaryotic species, indicating that it performs a basal cellular function. However, differential tissue expression and the existence of several ACBP paralogues in many eukaryotic species indicate that these proteins serve distinct functions. The nematode Caenorhabditis elegans expresses seven ACBPs: four basal forms and three ACBP domain proteins. We find that each of these paralogues is capable of complementing the growth of ACBP-deficient yeast cells, and that they exhibit distinct temporal and tissue expression patterns in C. elegans. We have obtained loss-of-function mutants for six of these forms. All single mutants display relatively subtle phenotypes; however, we find that functional loss of ACBP-1 leads to reduced triacylglycerol (triglyceride) levels and aberrant lipid droplet morphology and number in the intestine. We also show that worms lacking ACBP-2 show a severe decrease in the ß-oxidation of unsaturated fatty acids. A quadruple mutant, lacking all basal ACBPs, is slightly developmentally delayed, displays abnormal intestinal lipid storage, and increased ß-oxidation. Collectively, the present results suggest that each of the ACBP paralogues serves a distinct function in C. elegans.


Assuntos
Inibidor da Ligação a Diazepam/metabolismo , Isoformas de Proteínas/genética , Sequência de Aminoácidos , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/fisiologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Ácidos Graxos Insaturados/metabolismo , Metabolismo dos Lipídeos , Dados de Sequência Molecular , Mutação , Isoformas de Proteínas/metabolismo , Receptores Citoplasmáticos e Nucleares/fisiologia , Inanição/metabolismo , Fatores de Transcrição/fisiologia , Triglicerídeos/metabolismo
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