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1.
Breast Cancer Res Treat ; 135(2): 505-17, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22875744

RESUMO

Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in DNA repair. PARP inhibitors can act as chemosensitizers, or operate on the principle of synthetic lethality when used as single agent. Clinical trials have shown drugs in this class to be promising for BRCA mutation carriers. We postulated that inability to demonstrate response in non-BRCA carriers in which BRCA is inactivated by other mechanisms or with deficiency in homologous recombination for DNA repair is due to lack of molecular markers that define a responding subpopulation. We identified candidate markers for this purpose for olaparib (AstraZeneca) by measuring inhibitory effects of nine concentrations of olaparib in 22 breast cancer cell lines and identifying features in transcriptional and genome copy number profiles that were significantly correlated with response. We emphasized in this discovery process genes involved in DNA repair. We found that the cell lines that were sensitive to olaparib had a significant lower copy number of BRCA1 compared to the resistant cell lines (p value 0.012). In addition, we discovered seven genes from DNA repair pathways whose transcriptional levels were associated with response. These included five genes (BRCA1, MRE11A, NBS1, TDG, and XPA) whose transcript levels were associated with resistance and two genes (CHEK2 and MK2) whose transcript levels were associated with sensitivity. We developed an algorithm to predict response using the seven-gene transcription levels and applied it to 1,846 invasive breast cancer samples from 8 U133A/plus 2 (Affymetrix) data sets and found that 8-21 % of patients would be predicted to be responsive to olaparib. A similar response frequency was predicted in 536 samples analyzed on an Agilent platform. Importantly, tumors predicted to respond were enriched in basal subtype tumors. Our studies support clinical evaluation of the utility of our seven-gene signature as a predictor of response to olaparib.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasia de Células Basais/tratamento farmacológico , Ftalazinas/farmacologia , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Reparo do DNA/genética , Avaliação Pré-Clínica de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Expressão Gênica , Humanos , Concentração Inibidora 50 , Poli(ADP-Ribose) Polimerase-1 , Estatísticas não Paramétricas , Transcriptoma
3.
Genome Biol ; 14(10): R110, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24176112

RESUMO

BACKGROUND: First-generation molecular profiles for human breast cancers have enabled the identification of features that can predict therapeutic response; however, little is known about how the various data types can best be combined to yield optimal predictors. Collections of breast cancer cell lines mirror many aspects of breast cancer molecular pathobiology, and measurements of their omic and biological therapeutic responses are well-suited for development of strategies to identify the most predictive molecular feature sets. RESULTS: We used least squares-support vector machines and random forest algorithms to identify molecular features associated with responses of a collection of 70 breast cancer cell lines to 90 experimental or approved therapeutic agents. The datasets analyzed included measurements of copy number aberrations, mutations, gene and isoform expression, promoter methylation and protein expression. Transcriptional subtype contributed strongly to response predictors for 25% of compounds, and adding other molecular data types improved prediction for 65%. No single molecular dataset consistently out-performed the others, suggesting that therapeutic response is mediated at multiple levels in the genome. Response predictors were developed and applied to TCGA data, and were found to be present in subsets of those patient samples. CONCLUSIONS: These results suggest that matching patients to treatments based on transcriptional subtype will improve response rates, and inclusion of additional features from other profiling data types may provide additional benefit. Further, we suggest a systems biology strategy for guiding clinical trials so that patient cohorts most likely to respond to new therapies may be more efficiently identified.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Genômica , Modelos Biológicos , Proteômica , Algoritmos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Prognóstico , Splicing de RNA , Reprodutibilidade dos Testes , Transdução de Sinais , Máquina de Vetores de Suporte , Resultado do Tratamento
4.
PLoS One ; 7(12): e51786, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23251624

RESUMO

SATB1 drives metastasis when expressed in breast tumor cells by radically reprogramming gene expression. Here, we show that SATB1 also has an oncogenic activity to transform certain non-malignant breast epithelial cell lines. We studied the non-malignant MCF10A cell line, which is used widely in the literature. We obtained aliquots from two different sources (here we refer to them as MCF10A-1 and MCF10A-2), but found them to be surprisingly dissimilar in their responses to oncogenic activity of SATB1. Ectopic expression of SATB1 in MCF10A-1 induced tumor-like morphology in three-dimensional cultures, led to tumor formation in immunocompromised mice, and when injected into tail veins, led to lung metastasis. The number of metastases correlated positively with the level of SATB1 expression. In contrast, SATB1 expression in MCF10A-2 did not lead to any of these outcomes. Yet DNA copy-number analysis revealed that MCF10A-1 is indistinguishable genetically from MCF10A-2. However, gene expression profiling analysis revealed that these cell lines have significantly divergent signatures for the expression of genes involved in oncogenesis, including cell cycle regulation and signal transduction. Above all, the early DNA damage-response kinase, ATM, was greatly reduced in MCF10A-1 cells compared to MCF10A-2 cells. We found the reason for reduction to be phenotypic drift due to long-term cultivation of MCF10A. ATM knockdown in MCF10A-2 and two other non-malignant breast epithelial cell lines, 184A1 and 184B4, enabled SATB1 to induce malignant phenotypes similar to that observed for MCF10A-1. These data indicate a novel role for ATM as a suppressor of SATB1-induced malignancy in breast epithelial cells, but also raise a cautionary note that phenotypic drift could lead to dramatically different functional outcomes.


Assuntos
Mama/patologia , Proteínas de Ciclo Celular/metabolismo , Transformação Celular Neoplásica/patologia , Proteínas de Ligação a DNA/metabolismo , Progressão da Doença , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Proteínas Mutadas de Ataxia Telangiectasia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Pulmão/patologia , Camundongos , Camundongos Nus , Células NIH 3T3 , Invasividade Neoplásica , Fenótipo
5.
Cancer Discov ; 1(2): 137-43, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21984974

RESUMO

Timely intervention for cancer requires knowledge of its earliest genetic aberrations. Sequencing of tumors and their metastases reveals numerous abnormalities occurring late in progression. A means to temporally order aberrations in a single cancer, rather than inferring them from serially acquired samples, would define changes preceding even clinically evident disease. We integrate DNA sequence and copy number information to reconstruct the order of abnormalities as individual tumors evolve for 2 separate cancer types. We detect vast, unreported expansion of simple mutations sharply demarcated by recombinative loss of the second copy of TP53 in cutaneous squamous cell carcinomas (cSCC) and serous ovarian adenocarcinomas, in the former surpassing 50 mutations per megabase. In cSCCs, we also report diverse secondary mutations in known and novel oncogenic pathways, illustrating how such expanded mutagenesis directly promotes malignant progression. These results reframe paradigms in which TP53 mutation is required later, to bypass senescence induced by driver oncogenes.


Assuntos
Carcinoma de Células Escamosas/genética , Transformação Celular Neoplásica/genética , Cistadenocarcinoma Seroso/genética , Neoplasias Ovarianas/genética , Carcinoma de Células Escamosas/patologia , Transformação Celular Neoplásica/patologia , Aberrações Cromossômicas , Cistadenocarcinoma Seroso/patologia , Progressão da Doença , Feminino , Humanos , Mutação , Oncogenes , Neoplasias Ovarianas/patologia , Proteína Supressora de Tumor p53/genética
6.
Cancer Res ; 69(19): 7826-34, 2009 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-19789341

RESUMO

Inherent cancer phenotypes that are independent of fluctuating cross-talk with the surrounding tissue matrix are highly desirable candidates for targeting tumor cells. Our novel study design uses epithelial cell lines derived from low versus high histologic grade primary breast cancer to effectively diminish the breadth of transient variability generated within the tumor microenvironment of the host, revealing a "paracrine-independent expression of grade-associated" (PEGA) gene signature. PEGA members extended beyond "proliferation-driven" signatures commonly associated with aggressive, high-grade breast cancer. The calcium-binding protein S100P was prominent among PEGA genes overexpressed in high-grade tumors. A three-member fingerprint of S100P-correlated genes, consisting of GPRC5A, FXYD3, and PYCARD, conferred poor outcome in multiple breast cancer data sets, irrespective of estrogen receptor status but dependent on tumor size (P < 0.01). S100P silencing markedly diminished coregulated gene transcripts and reversed aggressive tumor behavior. Exposure to pathway-implicated agents, including the calmodulin inhibitor N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, phenothiazine, and chlorpromazine, resulted in rapid apoptotic cell death in high-grade tumor cells resistant to the chemotherapeutic drug cisplatin. This is the first comprehensive study describing molecular phenotypes intimately associated with histologic grade whose expression remains relatively fixed despite an unavoidably changing environment to which tumor cells are invariably exposed.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Adulto , Idoso , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Proteínas de Ligação ao Cálcio/biossíntese , Proteínas de Ligação ao Cálcio/genética , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Perfilação da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Células Tumorais Cultivadas
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