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1.
EMBO J ; 39(19): e104063, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32790115

RESUMO

The tumour stroma regulates nearly all stages of carcinogenesis. Stromal heterogeneity in human triple-negative breast cancers (TNBCs) remains poorly understood, limiting the development of stromal-targeted therapies. Single-cell RNA sequencing of five TNBCs revealed two cancer-associated fibroblast (CAF) and two perivascular-like (PVL) subpopulations. CAFs clustered into two states: the first with features of myofibroblasts and the second characterised by high expression of growth factors and immunomodulatory molecules. PVL cells clustered into two states consistent with a differentiated and immature phenotype. We showed that these stromal states have distinct morphologies, spatial relationships and functional properties in regulating the extracellular matrix. Using cell signalling predictions, we provide evidence that stromal-immune crosstalk acts via a diverse array of immunoregulatory molecules. Importantly, the investigation of gene signatures from inflammatory-CAFs and differentiated-PVL cells in independent TNBC patient cohorts revealed strong associations with cytotoxic T-cell dysfunction and exclusion, respectively. Such insights present promising candidates to further investigate for new therapeutic strategies in the treatment of TNBCs.


Assuntos
Neoplasias de Mama Triplo Negativas/imunologia , Evasão Tumoral , Matriz Extracelular/imunologia , Matriz Extracelular/patologia , Feminino , Humanos , RNA-Seq , Células Estromais/imunologia , Células Estromais/patologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia , Neoplasias de Mama Triplo Negativas/patologia
2.
Breast Cancer Res ; 22(1): 87, 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32787886

RESUMO

BACKGROUND: Resistance to endocrine therapy is a major clinical challenge in the management of oestrogen receptor (ER)-positive breast cancer. In this setting, p53 is frequently wildtype and its activity may be suppressed via upregulation of its key regulator MDM2. This underlies our rationale to evaluate MDM2 inhibition as a therapeutic strategy in treatment-resistant ER-positive breast cancer. METHODS: We used the MDM2 inhibitor NVP-CGM097 to treat in vitro and in vivo models alone and in combination with fulvestrant or palbociclib. We perform cell viability, cell cycle, apoptosis and senescence assays to evaluate anti-tumour effects in p53 wildtype and p53 mutant ER-positive cell lines (MCF-7, ZR75-1, T-47D) and MCF-7 lines resistant to endocrine therapy and to CDK4/6 inhibition. We further assess the drug effects in patient-derived xenograft (PDX) models of endocrine-sensitive and endocrine-resistant ER-positive breast cancer. RESULTS: We demonstrate that MDM2 inhibition results in cell cycle arrest and increased apoptosis in p53-wildtype in vitro and in vivo breast cancer models, leading to potent anti-tumour activity. We find that endocrine therapy or CDK4/6 inhibition synergises with MDM2 inhibition but does not further enhance apoptosis. Instead, combination treatments result in profound regulation of cell cycle-related transcriptional programmes, with synergy achieved through increased antagonism of cell cycle progression. Combination therapy pushes cell lines resistant to fulvestrant or palbociclib to become senescent and significantly reduces tumour growth in a fulvestrant-resistant patient-derived xenograft model. CONCLUSIONS: We conclude that MDM2 inhibitors in combination with ER degraders or CDK4/6 inhibitors represent a rational strategy for treating advanced, endocrine-resistant ER-positive breast cancer, operating through synergistic activation of cell cycle co-regulatory programmes.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Receptores de Estrogênio/metabolismo , Animais , Apoptose , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Fulvestranto/administração & dosagem , Humanos , Isoquinolinas/administração & dosagem , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Piperazinas/administração & dosagem , Piridinas/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Adv Sci (Weinh) ; 11(23): e2307963, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38602451

RESUMO

In recent decades, the role of tumor biomechanics on cancer cell behavior at the primary site has been increasingly appreciated. However, the effect of primary tumor biomechanics on the latter stages of the metastatic cascade, such as metastatic seeding of secondary sites and outgrowth remains underappreciated. This work sought to address this in the context of triple negative breast cancer (TNBC), a cancer type known to aggressively disseminate at all stages of disease progression. Using mechanically tuneable model systems, mimicking the range of stiffness's typically found within breast tumors, it is found that, contrary to expectations, cancer cells exposed to softer microenvironments are more able to colonize secondary tissues. It is shown that heightened cell survival is driven by enhanced metabolism of fatty acids within TNBC cells exposed to softer microenvironments. It is demonstrated that uncoupling cellular mechanosensing through integrin ß1 blocking antibody effectively causes stiff primed TNBC cells to behave like their soft counterparts, both in vitro and in vivo. This work is the first to show that softer tumor microenvironments may be contributing to changes in disease outcome by imprinting on TNBC cells a greater metabolic flexibility and conferring discrete cell survival advantages.


Assuntos
Ácidos Graxos , Neoplasias de Mama Triplo Negativas , Microambiente Tumoral , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Humanos , Feminino , Ácidos Graxos/metabolismo , Camundongos , Linhagem Celular Tumoral , Animais , Fenômenos Biomecânicos , Modelos Animais de Doenças , Metástase Neoplásica
4.
Drug Des Devel Ther ; 16: 2933-2948, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36081610

RESUMO

Several endocrine therapies are currently available for the treatment of estrogen receptor (ER) positive breast cancer, but the clinical benefit of these agents is limited by endocrine therapy drug resistance. A common mechanism of endocrine therapy resistance is ESR1 mutations. The first-generation selective estrogen receptor degrader (SERD) fulvestrant has activity against ESR1 mutant tumors but requires intramuscular injection and has poor bioavailability that precludes optimal drug dosing. This led to the development of second-generation SERDs which are potent and have improved oral bioavailability and pharmacokinetics. Several of these oral SERDs are now in phase III trials in both the early and advanced ER positive breast cancer settings. This review summarizes the background of oral SERD development, the current status and future perspectives.


Assuntos
Neoplasias da Mama , Neoplasias Bucais , Mama , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/genética , Feminino , Humanos , Receptores de Estrogênio , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico
5.
Cancers (Basel) ; 14(4)2022 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-35205665

RESUMO

Endocrine therapy forms the backbone of systemic therapy for the majority of persons with early and late-stage breast cancer. However, the side effects can negatively affect quality of life, and impact treatment adherence and overall oncological outcomes. Adverse effects on cognition are common, underreported and challenging to manage. We aim to describe the nature, incidence, risk factors and underlying mechanisms of endocrine therapy-induced cognitive dysfunction. We conducted a comprehensive literature review of the studies reporting on cognitive dysfunction associated with endocrine therapies for breast cancer. We also summarise prevention and treatment strategies, and ongoing research. Given that patients are taking endocrine therapies for longer durations than ever before, it is essential that these side effects are managed pro-actively within a multi-disciplinary team in order to promote adherence to endocrine therapy and improve patients' quality of life.

6.
Genes (Basel) ; 12(2)2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33671468

RESUMO

Systemic treatment of hormone receptor-positive (HR+) breast cancer is undergoing a renaissance, with a number of targeted therapies including CDK4/6, mTOR, and PI3K inhibitors now approved for use in combination with endocrine therapies. The increased use of targeted therapies has changed the natural history of HR+ breast cancers, with the emergence of new escape mechanisms leading to the inevitable progression of disease in patients with advanced cancers. The identification of new predictive and pharmacodynamic biomarkers to current standard-of-care therapies and discovery of new therapies is an evolving and urgent clinical challenge in this setting. While traditional, routinely measured biomarkers such as estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2) still represent the best prognostic and predictive biomarkers for HR+ breast cancer, a significant proportion of patients either do not respond to endocrine therapy or develop endocrine resistant disease. Genomic tests have emerged as a useful adjunct prognostication tool and guide the addition of chemotherapy to endocrine therapy. In the treatment-resistant setting, mutational profiling has been used to identify ESR1, PIK3CA, and AKT mutations as predictive molecular biomarkers to newer therapies. Additionally, pharmacodynamic biomarkers are being increasingly used and considered in the metastatic setting. In this review, we summarise the current state-of-the-art therapies; prognostic, predictive, and pharmacodynamic molecular biomarkers; and how these are impacted by emerging therapies for HR+ breast cancer.


Assuntos
Neoplasias da Mama/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Receptor alfa de Estrogênio/genética , Proteína Oncogênica v-akt/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Hormônios/uso terapêutico , Humanos , Metástase Neoplásica , Prognóstico , Receptor ErbB-2/genética , Receptores de Estrogênio/genética , Receptores de Progesterona/genética
7.
Genome Med ; 13(1): 81, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33971952

RESUMO

BACKGROUND: High throughput single-cell RNA sequencing (scRNA-Seq) has emerged as a powerful tool for exploring cellular heterogeneity among complex human cancers. scRNA-Seq studies using fresh human surgical tissue are logistically difficult, preclude histopathological triage of samples, and limit the ability to perform batch processing. This hindrance can often introduce technical biases when integrating patient datasets and increase experimental costs. Although tissue preservation methods have been previously explored to address such issues, it is yet to be examined on complex human tissues, such as solid cancers and on high throughput scRNA-Seq platforms. METHODS: Using the Chromium 10X platform, we sequenced a total of ~ 120,000 cells from fresh and cryopreserved replicates across three primary breast cancers, two primary prostate cancers and a cutaneous melanoma. We performed detailed analyses between cells from each condition to assess the effects of cryopreservation on cellular heterogeneity, cell quality, clustering and the identification of gene ontologies. In addition, we performed single-cell immunophenotyping using CITE-Seq on a single breast cancer sample cryopreserved as solid tissue fragments. RESULTS: Tumour heterogeneity identified from fresh tissues was largely conserved in cryopreserved replicates. We show that sequencing of single cells prepared from cryopreserved tissue fragments or from cryopreserved cell suspensions is comparable to sequenced cells prepared from fresh tissue, with cryopreserved cell suspensions displaying higher correlations with fresh tissue in gene expression. We showed that cryopreservation had minimal impacts on the results of downstream analyses such as biological pathway enrichment. For some tumours, cryopreservation modestly increased cell stress signatures compared to freshly analysed tissue. Further, we demonstrate the advantage of cryopreserving whole-cells for detecting cell-surface proteins using CITE-Seq, which is impossible using other preservation methods such as single nuclei-sequencing. CONCLUSIONS: We show that the viable cryopreservation of human cancers provides high-quality single-cells for multi-omics analysis. Our study guides new experimental designs for tissue biobanking for future clinical single-cell RNA sequencing studies.


Assuntos
Bancos de Espécimes Biológicos , Criopreservação , Genômica , Neoplasias/diagnóstico , Análise de Célula Única , Biomarcadores Tumorais , Criopreservação/métodos , Criopreservação/normas , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunofenotipagem , Neoplasias/etiologia , Especificidade de Órgãos/genética , Análise de Sequência de RNA/métodos , Transdução de Sinais , Análise de Célula Única/métodos
8.
Nat Genet ; 53(9): 1334-1347, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34493872

RESUMO

Breast cancers are complex cellular ecosystems where heterotypic interactions play central roles in disease progression and response to therapy. However, our knowledge of their cellular composition and organization is limited. Here we present a single-cell and spatially resolved transcriptomics analysis of human breast cancers. We developed a single-cell method of intrinsic subtype classification (SCSubtype) to reveal recurrent neoplastic cell heterogeneity. Immunophenotyping using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) provides high-resolution immune profiles, including new PD-L1/PD-L2+ macrophage populations associated with clinical outcome. Mesenchymal cells displayed diverse functions and cell-surface protein expression through differentiation within three major lineages. Stromal-immune niches were spatially organized in tumors, offering insights into antitumor immune regulation. Using single-cell signatures, we deconvoluted large breast cancer cohorts to stratify them into nine clusters, termed 'ecotypes', with unique cellular compositions and clinical outcomes. This study provides a comprehensive transcriptional atlas of the cellular architecture of breast cancer.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Análise de Célula Única , Transcriptoma/genética , Linfócitos B/imunologia , Antígeno B7-H1/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Endoteliais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Macrófagos/citologia , Macrófagos/imunologia , Proteínas de Membrana/genética , Células Mieloides/imunologia , Células Mieloides/metabolismo , Análise de Sequência de RNA , Microambiente Tumoral , Proteínas Supressoras de Tumor/genética
9.
Int J Cancer ; 126(6): 1445-53, 2010 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-19676041

RESUMO

The phospholipid transfer protein STARD10 cooperates with c-erbB signaling and is overexpressed in Neu/ErbB2 breast cancers. We investigated if STARD10 expression provides additional prognostic information to HER2/neu status in primary breast cancer. A published gene expression dataset was used to determine relationships between STARD10 and HER2 mRNA levels and patient outcome. The central findings were independently validated by immunohistochemistry in a retrospective cohort of 222 patients with breast cancer with a median follow-up of 64 months. Kaplan-Meier and Cox proportional hazards analyses were used for univariate and multivariate analyses. Patients with low STARD10 or high HER2 tumor mRNA levels formed discrete groups each associated with a poor disease-specific survival (p = 0.0001 and p = 0.0058, respectively). In the immunohistochemical study low/absent STARD10 expression i.e. < or = 10% positive cells was observed in 24 of 222 (11%) tumors. In a univariate model, low/absent STARD10 expression was significantly associated with decreased patient survival (p = 0.0008). In multivariate analyses incorporating tumor size, tumor grade, lymph node status, ER, PR and HER2 status, low STARD10 expression was an independent predictor of death from breast cancer (HR: 2.56 (95% CI: 1.27-5.18), p = 0.0086). Furthermore, low/absent STARD10 expression, HER2 amplification and triple negative status were independent prognostic variables. Loss of STARD10 expression may provide an additional marker of poor outcome in breast cancer identifying a subgroup of patients with a particularly adverse prognosis, which is independent of HER2 amplification and the triple negative phenotype.


Assuntos
Neoplasias da Mama/patologia , Fosfoproteínas/metabolismo , Receptor ErbB-2/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Estudos de Coortes , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Metástase Linfática , Análise Multivariada , Fosfoproteínas/genética , Prognóstico , Receptor ErbB-2/genética , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos
10.
Gastroenterology ; 137(2): 558-68, 568.e1-11, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19376121

RESUMO

BACKGROUND & AIMS: Current methods of preoperative staging and predicting outcome following pancreatectomy for pancreatic cancer (PC) are inadequate. We evaluated the utility of multiple biomarkers from distinct biologic pathways as potential predictive markers of response to pancreatectomy and patient survival. METHODS: We assessed the relationship of candidate biomarkers known, or suspected, to be aberrantly expressed in PC, with disease-specific survival and response to therapy in a cohort of 601 patients. RESULTS: Of the 17 candidate biomarkers examined, only elevated expression of S100A2 was an independent predictor of survival in both the training (n = 162) and validation sets (n = 439; hazard ratio [HR], 2.19; 95% confidence interval [CI]: 1.48-3.25; P < .0001) when assessed in a multivariate model with clinical variables. Patients with high S100A2 expressing tumors had no survival benefit with pancreatectomy compared with those with locally advanced disease, whereas those without high S100A2 expression had a survival advantage of 10.6 months (19.4 vs 8.8 months, respectively) and a HR of 3.23 (95% CI: 2.39-4.33; P < .0001). Of significance, patients with S100A2-negative tumors had a significant survival benefit from pancreatectomy even in the presence of involved surgical margins (median, 15.7 months; P = .0007) or lymph node metastases (median, 17.4 months; P = .0002). CONCLUSIONS: S100A2 expression is a good predictor of response to pancreatectomy for PC and suggests that high S100A2 expression may be a marker of a metastatic phenotype. Prospective measurement of S100A2 expression in diagnostic biopsy samples has potential clinical utility as a predictive marker of response to pancreatectomy and other therapies that target locoregional disease.


Assuntos
Adenocarcinoma/cirurgia , Biomarcadores Tumorais/metabolismo , Pancreatectomia/mortalidade , Neoplasias Pancreáticas/cirurgia , Proteínas S100/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Estudos de Coortes , Intervalos de Confiança , Intervalo Livre de Doença , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pancreatectomia/métodos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Complicações Pós-Operatórias/mortalidade , Valor Preditivo dos Testes , Probabilidade , Modelos de Riscos Proporcionais , Medição de Risco , Proteínas S100/genética , Sensibilidade e Especificidade , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento
11.
Ann Surg Oncol ; 17(7): 1841-6, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20143266

RESUMO

BACKGROUND: Axillary lymph node status provides important staging information. We sought to evaluate the predictive value of breast magnetic resonance imaging (MRI) in detecting axillary lymph node metastases prior to initiation of neoadjuvant chemotherapy (NAC) and in detecting residual lymph node metastases after NAC in women found to be node positive prior to NAC. METHODS: Women underwent breast MRI with axillary evaluation prior to initiation of NAC and again after completion of NAC. Pathologic confirmation of lymph node status was confirmed by sentinel lymph node biopsy (SLNB), image-guided axillary fine-needle aspiration (FNA)/core biopsy, or axillary lymph node dissection. We evaluated the sensitivity, specificity, and negative and positive predictive values of MRI in detecting axillary node involvement. RESULTS: Seventy-four women completed NAC and underwent surgery. Sensitivity of MRI in detecting axillary node involvement prior to NAC was 64.7% and specificity was 100%, with positive and negative predictive values of MRI of 100% and 77.8%, respectively. Sensitivity and specificity of MRI to identify residual pathologic axillary lymph node disease following NAC were 85.7% and 89%, respectively, while the positive and negative predictive values were 92% and 80.9%, respectively. CONCLUSION: Breast MRI has moderate sensitivity and high specificity for predicting axillary lymph node status prior to NAC. In patients found to be node positive prior to NAC, MRI was able to predict with moderate sensitivity and specificity whether residual nodal disease was present. The accuracy of MRI is not adequate to obviate either the need for staging by sentinel node biopsy or the need for completion axillary dissection in women determined to be node positive prior to NAC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Imageamento por Ressonância Magnética , Terapia Neoadjuvante , Adulto , Idoso , Axila , Biópsia por Agulha Fina , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Sensibilidade e Especificidade , Biópsia de Linfonodo Sentinela , Taxa de Sobrevida , Resultado do Tratamento
12.
ANZ J Surg ; 90(1-2): 34-40, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31770829

RESUMO

Window of opportunity therapies, which involve short-term administration of systemic therapy between cancer diagnosis and surgery, have raised significant interest in recent years as a mean of assessing the sensitivity of a patient's cancer to therapy prior to surgery. There is now compelling evidence that in patients with early stage hormone-receptor positive breast cancer, a 2-week preoperative treatment with standard hormone therapies in a preoperative window period provides important prognostic information, which in turn helps to aid decision-making regarding treatment options. Changes in short-term biomarker endpoints such as cell proliferation measured by Ki-67 can act as surrogate markers of long-term outcomes. Paired tissues obtained pre- and post-investigational treatment, without having to subject the patient to additional biopsies, can then be used to conduct translational research to investigate predictive biomarkers and pharmacodynamics. In this review, we will examine the utility and challenges of window of opportunities therapies in breast cancer in the current literature, and the current Australian and international trial landscape in this clinical space.


Assuntos
Neoplasias da Mama/terapia , Antineoplásicos/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Biomarcadores Tumorais , Terapia Combinada , Medicina Baseada em Evidências , Feminino , Humanos , Mastectomia , Terapia Neoadjuvante , Prognóstico
13.
Endocr Relat Cancer ; 26(2): 251-264, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30557851

RESUMO

The role of androgen receptor (AR) in endocrine-resistant breast cancer is controversial and clinical trials targeting AR with an AR antagonist (e.g., enzalutamide) have been initiated. Here, we investigated the consequence of AR antagonism using in vitro and in vivo models of endocrine resistance. AR antagonism in MCF7-derived tamoxifen-resistant (TamR) and long-term estrogen-deprived breast cancer cell lines were achieved using siRNA-mediated knockdown or pharmacological inhibition with enzalutamide. The efficacy of enzalutamide was further assessed in vivo in an estrogen-independent endocrine-resistant patient-derived xenograft (PDX) model. Knockdown of AR inhibited the growth of the endocrine-resistant cell line models. Microarray gene expression profiling of the TamR cells following AR knockdown revealed perturbations in proliferative signaling pathways upregulated in endocrine resistance. AR loss also increased some canonical ER signaling events and restored sensitivity of TamR cells to tamoxifen. In contrast, enzalutamide did not recapitulate the effect of AR knockdown in vitro, even though it inhibited canonical AR signaling, which suggests that it is the non-canonical AR activity that facilitated endocrine resistance. Enzalutamide had demonstrable efficacy in inhibiting AR activity in vivo but did not affect the growth of the endocrine-resistant PDX model. Our findings implicate non-canonical AR activity in facilitating an endocrine-resistant phenotype in breast cancer. Unlike canonical AR signaling which is inhibited by enzalutamide, non-canonical AR activity is not effectively antagonized by enzalutamide, and this has important implications in the design of future AR-targeted clinical trials in endocrine-resistant breast cancer.


Assuntos
Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , Receptores Androgênicos/genética , Antagonistas de Receptores de Andrógenos/uso terapêutico , Animais , Antineoplásicos Hormonais/uso terapêutico , Benzamidas , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Camundongos , Nitrilas , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , RNA Interferente Pequeno/genética , Receptores de Estrogênio/metabolismo , Tamoxifeno/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Acta Cytol ; 63(4): 257-273, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31112942

RESUMO

The International Academy of Cytology (IAC) gathered together a group of cytopathologists expert in breast cytology who, working with clinicians expert in breast diagnostics and management, have developed the IAC Yokohama System for Reporting Breast Fine-Needle Aspiration Biopsy (FNAB) Cytology. The project was initiated with the first cytopathology group meeting in Yokohama at the 2016 International Congress of Cytology. This IAC Yokohama System defines five categories for reporting breast cytology, each with a clear descriptive term for the category, a definition, a risk of malignancy (ROM) and a suggested management algorithm. The key diagnostic cytopathology features of each of the lesions within each category will be presented more fully in a subsequent atlas. The System emphasizes that the crucial requirements for diagnostic breast FNAB cytology are a high standard for the performance of the FNAB and for the making of direct smears, and well-trained experienced cytopathologists to interpret the material. The performance indicators of breast FNAB, including specificity and sensitivity, negative predictive value, positive predictive value and ROM stated in this article have been derived from the recent literature. The current practice of breast FNAB has evolved with the increasing use of ultrasound guidance and rapid on-site evaluation. Two recent publications have shown a range of ROM for the insufficient/inadequate category of 2.6-4.8%, benign 1.4-2.3%, atypical 13-15.7%, suspicious of malignancy 84.6-97.1%, and malignant 99.0-100%. The management algorithm in the System provides options because there are variations in the management of breast lesions using FNAB and core-needle biopsy in those countries utilizing the "triple test" of clinical, imaging, and FNAB assessment, and also variations in the availability of CNB and imaging in low- and middle-income countries. The System will stimulate further discussion and research, particularly in the cytological diagnostic features of specific lesions within each category and in management recommendations. This will lead to continuing improvements in the care of patients with breast lesions and possible modifications to the IAC Yokohama System.


Assuntos
Neoplasias da Mama/diagnóstico , Citodiagnóstico/normas , Guias de Prática Clínica como Assunto/normas , Garantia da Qualidade dos Cuidados de Saúde , Biópsia por Agulha Fina , Neoplasias da Mama/cirurgia , Feminino , Humanos , Sociedades Médicas
15.
Cancer Epidemiol Biomarkers Prev ; 15(10): 1941-7, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17035403

RESUMO

The association of high cyclin E expression with poor outcome in some cancers, in particular breast cancer, suggests that it may play an important role in tumor biology. Because the influence of cyclin E expression on outcome is yet to be examined in pancreatic cancer, we assessed the relationship between the expression of cyclin E, p27(Kip1), and survival in a large cohort of pancreatic cancer patients with long-term follow-up. Expression of cyclin E and p27(Kip1) was assessed by immunohistochemistry using tissue microarrays of tumor samples from 118 patients with pancreatic ductal adenocarcinoma (75 resections and 43 biopsies). High cyclin E expression (>10% positive nuclei) was identified in 39 of 118 (33%) patients. This was associated with poor prognosis on univariate analysis in the whole cohort (P = 0.005), as well as in the subgroup of 75 patients who underwent operative resection (P = 0.04). On multivariate analysis, high cyclin E expression was an independent predictor of poor survival in both the entire cohort (P = 0.005) and the resected subgroup (P = 0.03), and was superior to all tested clinicopathologic factors (tumor size, lymph node metastases, differentiation, margin involvement, and perineural invasion) as a marker of survival. Low p27(Kip1) expression (<5% positive nuclei) was present in 41 of 111 (37%) patients, but was not associated with survival, and coexpression of p27(Kip1) did not influence the association of high cyclin E expression with poor survival. High cyclin E expression is a strong independent predictor of poor outcome in patients with pancreatic cancer. Thus, if these data are confirmed in independent cohorts, measurement of cyclin E may add significant prognostic information to the currently used clinicopathologic variables and hence have potential clinical utility in the management of this disease.


Assuntos
Adenocarcinoma/química , Adenocarcinoma/patologia , Biomarcadores Tumorais/análise , Ciclina E/análise , Ductos Pancreáticos/química , Ductos Pancreáticos/patologia , Neoplasias Pancreáticas/química , Neoplasias Pancreáticas/patologia , Adenocarcinoma/mortalidade , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Austrália , Inibidor de Quinase Dependente de Ciclina p27/análise , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pancreatectomia , Ductos Pancreáticos/cirurgia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/cirurgia , Valor Preditivo dos Testes , Prognóstico , Análise de Sobrevida , Resultado do Tratamento
16.
Clin Cancer Res ; 11(9): 3587-96, 2005 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-15867264

RESUMO

PURPOSE: Despite significant progress in understanding the molecular pathology of pancreatic cancer and its precursor lesion: pancreatic intraepithelial neoplasia (PanIN), there remain no molecules with proven clinical utility as prognostic or therapeutic markers. Here, we used oligonucleotide microarrays to interrogate mRNA expression of pancreatic cancer tissue and normal pancreas to identify novel molecular pathways dysregulated in the development and progression of pancreatic cancer. EXPERIMENTAL DESIGN: RNA was hybridized to Affymetrix Genechip HG-U133 oligonucleotide microarrays. A relational database integrating data from publicly available resources was created to identify candidate genes potentially relevant to pancreatic cancer. The protein expression of one candidate, homeobox B2 (HOXB2), in PanIN and pancreatic cancer was assessed using immunohistochemistry. RESULTS: We identified aberrant expression of several components of the retinoic acid (RA) signaling pathway (RARalpha, MUC4, Id-1, MMP9, uPAR, HB-EGF, HOXB6, and HOXB2), many of which are known to be aberrantly expressed in pancreatic cancer and PanIN. HOXB2, a downstream target of RA, was up-regulated 6.7-fold in pancreatic cancer compared with normal pancreas. Immunohistochemistry revealed ectopic expression of HOXB2 in 15% of early PanIN lesions and 48 of 128 (38%) pancreatic cancer specimens. Expression of HOXB2 was associated with nonresectable tumors and was an independent predictor of poor survival in resected tumors. CONCLUSIONS: We identified aberrant expression of RA signaling components in pancreatic cancer, including HOXB2, which was expressed in a proportion of PanIN lesions. Ectopic expression of HOXB2 was associated with a poor prognosis for all patients with pancreatic cancer and was an independent predictor of survival in patients who underwent resection.


Assuntos
Perfilação da Expressão Gênica , Proteínas de Homeodomínio/genética , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Fatores de Transcrição/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Análise de Sequência com Séries de Oligonucleotídeos , Pâncreas/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Análise de Sobrevida , Fatores de Transcrição/metabolismo , Tretinoína/farmacologia
17.
Int J Surg ; 30: 116-20, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27142863

RESUMO

INTRODUCTION: Seroma formation in breast cancer patients who have undergone axillary lymph node dissection (ALND) is a source of significant discomfort and morbidity. We aimed to ascertain seroma incidence after ALND, when Harmonic Focus (HF) scalpel is used for dissection instead of conventional diathermy (CD). METHODS(AND PATIENTS): This retrospective study was carried out in a single hospital over 6 years. Patients were allocated into HF group (HFG) or CD group (CDG). Seroma volume, hospital stay, and complications were evaluated. RESULTS: Of 94 patients, 42 were in the HFG and 52 in the CDG. Two day median seroma volume was 205 ml (IQR 95-265) for HF, and 227.5 ml (IQR 149-385) for CD. The total median seroma output was 270 ml (IQR 160-478) for HF, and 385 ml (IQR 220-558) for CD. No statistically significant differences between HFG and CDG were identified in these data, as well as patient demographics, operative time, and complication rates. Duration of surgery >2.5 h increased seroma formation (p < 0.001). Mastectomy and ALND increased seroma formation compared to wide local excision (WLE) and ALND (p < 0.05). Nodal involvement, number of lymph nodes resected, and extra nodal spread did not influence seroma formation. DISCUSSION(AND CONCLUSION): In our hands, HF use was not superior to CD in limiting seroma formation in ALND for breast cancer. Increased seroma formation in surgeries >2.5 h in duration is commensurate with surgeries involving mastectomy and ALND (>2.5 h in our study), which entails greater and sustained tissue and lymphovascular trauma.


Assuntos
Neoplasias da Mama/cirurgia , Eletrocoagulação/instrumentação , Excisão de Linfonodo/efeitos adversos , Mastectomia/efeitos adversos , Seroma/prevenção & controle , Procedimentos Cirúrgicos Ultrassônicos/instrumentação , Axila , Dissecação/instrumentação , Drenagem , Feminino , Humanos , Excisão de Linfonodo/instrumentação , Pessoa de Meia-Idade , Estudos Retrospectivos , Seroma/etiologia , Seroma/terapia
18.
Oncogene ; 22(32): 5070-81, 2003 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-12902990

RESUMO

EDD (E3 isolated by differential display), located at chromosome 8q22.3, is the human orthologue of the Drosophila melanogaster tumour suppressor gene 'hyperplastic discs' and encodes a HECT domain E3 ubiquitin protein-ligase. To investigate the possible involvement of EDD in human cancer, several cancers from diverse tissue sites were analysed for allelic gain or loss (allelic imbalance, AI) at the EDD locus using an EDD-specific microsatellite, CEDD, and other polymorphic microsatellites mapped in the vicinity of the 8q22.3 locus. Of 143 cancers studied, 38 had AI at CEDD (42% of 90 informative cases). In 14 of these cases, discrete regions of imbalance encompassing 8q22.3 were present, while the remainder had more extensive 8q aberrations. AI of CEDD was most frequent in ovarian cancer (22/47 informative cases, 47%), particularly in the serous subtype (16/22, 73%), but was rare in benign and borderline ovarian tumours. AI was also common in breast cancer (31%), hepatocellular carcinoma (46%), squamous cell carcinoma of the tongue (50%) and metastatic melanoma (18%). AI is likely to represent amplification of the EDD gene locus rather than loss of heterozygosity, as quantitative RT-PCR and immunohistochemistry showed that EDD mRNA and protein are frequently overexpressed in breast and ovarian cancers, while among breast cancer cell lines EDD overexpression and increased gene copy number were correlated. These results demonstrate that AI at the EDD locus is common in a diversity of carcinomas and that the EDD gene is frequently overexpressed in breast and ovarian cancer, implying a potential role in cancer progression.


Assuntos
Neoplasias da Mama/genética , Neoplasias Ovarianas/genética , Peptídeo Sintases/genética , Ubiquitina-Proteína Ligases , Aberrações Cromossômicas , Cromossomos Humanos Par 8 , Feminino , Humanos , Repetições de Microssatélites , Neoplasias/genética , Peptídeo Sintases/biossíntese
20.
ANZ J Surg ; 83(3): 135-8, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23253050

RESUMO

BACKGROUND: Mastectomy for breast cancer treatment and prophylaxis has improved survival for patients. The advantage of implant reconstruction post mastectomy is that it avoids an additional donor site with its associated morbidity, which post-mastectomy autologous reconstruction necessitates. However, the deficiency of muscle coverage at the lower pole of the implant meant it relied on only skin envelope coverage, and thus has the established complication of implant exposure or infection should the skin break down. In 2006, Nava devised a technique for a single-stage reconstruction using definitive breast implants with two-layer coverage of the lower pole with a vascularized dermal layer, as well as the traditional skin envelope, in women with preoperative large ptotic breasts. We present our experience with single-stage implant breast reconstruction using this technique. METHOD: A retrospective review of the medical and operative records as well as patients' photographs was undertaken for consecutive patients from November 2009 to April 2011. These patients were selected for the procedure based on set criteria. We describe our surgical technique for this procedure. RESULT: In the 18-month period, 6 patients underwent 11 skin sparing reduction mastectomy (SSRM) implant reconstructions. Follow-up ranged from 5 to 19 months. The mean length of hospital stay was 7.2 days (range was 2-15 days). One breast out of 11 reconstructions developed an infected seroma 8 months post-operatively, requiring aspiration and intravenous antibiotics. One breast out of 11 developed T junction skin necrosis and associated cellulitis but the breast implant was protected by a visibly vascularized dermal flap and, thus, was not exposed. One breast developed a minor vertical wound dehiscence. CONCLUSION: In our initial experience, SSRM is a safe and effective method of immediate implant-based breast reconstruction.


Assuntos
Implante Mamário/métodos , Mastectomia/métodos , Adulto , Feminino , Humanos , Mamilos/cirurgia , Estudos Retrospectivos
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