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Cancer Res ; 73(12): 3483-8, 2013 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-23740772


Combinatorial approaches that integrate conventional pathology with genomic profiling and functional genomics have begun to enhance our understanding of the genetic basis of breast cancer. These methods have identified key genotypic-phenotypic correlations in different breast cancer subtypes that have led to the discovery of genetic dependencies that drive their behavior. Moreover, this knowledge has been applied to define novel tailored therapies for these groups of patients with cancer. With the current emphasis on characterizing the mutational repertoire of breast cancers by next-generation sequencing, the question remains as to what constitutes a driver event. By focusing efforts on homogenous subgroups of breast cancer and integrating orthogonal data-types combined with functional approaches, we can begin to unravel the heterogeneity and identify aberrations that can be therapeutically targeted.

Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Genómica/métodos , Neoplasias de la Mama/patología , Femenino , Estudios de Asociación Genética/métodos , Estudios de Asociación Genética/tendencias , Humanos , Terapia Molecular Dirigida/métodos , Terapia Molecular Dirigida/tendencias , Investigación Biomédica Traslacional/métodos , Investigación Biomédica Traslacional/tendencias
Breast Cancer Res Treat ; 135(2): 505-17, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22875744


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.

Antineoplásicos/farmacología , Biomarcadores de Tumor/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias Basocelulares/tratamiento farmacológico , Ftalazinas/farmacología , Piperazinas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Reparación del ADN/genética , Evaluación Preclínica de Medicamentos , Resistencia a Antineoplásicos , Femenino , Expresión Génica , Humanos , Concentración 50 Inhibidora , Poli(ADP-Ribosa) Polimerasa-1 , Estadísticas no Paramétricas , Transcriptoma
Mod Pathol ; 23(10): 1334-45, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20543821


PPM1D (protein phosphatase magnesium-dependent 1δ) maps to the 17q23.2 amplicon and is amplified in ∼8% of breast cancers. The PPM1D gene encodes a serine threonine phosphatase, which is involved in the regulation of several tumour suppressor pathways, including the p53 pathway. Along with others, we have recently shown that PPM1D is one of the drivers of the 17q23.2 amplicon and a promising therapeutic target. Here we investigate whether PPM1D is overexpressed when amplified in breast cancers and the correlations between PPM1D overexpression and amplification with clinicopathological features and survival of breast cancer patients from a cohort of 245 patients with invasive breast cancer treated with therapeutic surgery followed by adjuvant anthracycline-based chemotherapy. mRNA was extracted from representative sections of tumours containing >50% of tumour cells and subjected to TaqMan quantitative real-time PCR using primers for PPM1D and for two housekeeping genes. PPM1D overexpression was defined as the top quartile of expression levels. Chromogenic in situ hybridization with in-house-generated probes for PPM1D was performed. Amplification was defined as >50% of cancer cells with >5 signals per nucleus/large gene clusters. PPM1D overexpression and amplification were found in 25 and 6% of breast cancers, respectively. All cases harbouring PPM1D amplification displayed PPM1D overexpression. PPM1D overexpression was inversely correlated with expression of TOP2A, EGFR and cytokeratins 5/6 and 17. PPM1D amplification was significantly associated with HER2 overexpression, and HER2, TOP2A and CCND1 amplification. No association between PPM1D gene amplification and PPM1D mRNA overexpression with survival was observed. In conclusion, PPM1D is consistently overexpressed when amplified; however, PPM1D overexpression is more pervasive than gene amplification. PPM1D overexpression and amplification are associated with tumours displaying luminal or HER2 phenotypes. Co-amplification of PPM1D and HER2/TOP2A and CCND1 are not random events and may suggest the presence of a 'firestorm' genetic profile.

Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Fosfoproteínas Fosfatasas/genética , Neoplasias de la Mama/mortalidad , Femenino , Amplificación de Genes , Humanos , Inmunohistoquímica , Hibridación in Situ , Estimación de Kaplan-Meier , Pronóstico , Proteína Fosfatasa 2C , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Matrices Tisulares