Article

Novel agents for the prevention of breast cancer: targeting transcription factors and signal transduction pathways.

Breast Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
Journal of Mammary Gland Biology and Neoplasia (impact factor: 6.74). 02/2003; 8(1):45-73. pp.45-73
Source: PubMed

ABSTRACT Transformation of breast cells occurs through loss or mutation of tumor suppressor genes, or activation or amplification of oncogenes, leading to deregulation of signal transduction pathways, abnormal amplification of growth signals, and aberrant expression of genes that ultimately transform the cells into invasive cancer. The goal of cancer preventive therapy, or "chemoprevention," is to eliminate premalignant cells or to block the progression of normal cells into cancer. Multiple alterations in signal pathways and transcription factors are observed in mammary gland tumorigenesis. In particular, estrogen receptor (ER) deregulation plays a critical role in breast cancer development and progress, and targeting ER with selective ER modulators (SERMs) has achieved significant reduction of breast cancer incidence in women at high risk for breast cancer. However, not all breast cancer is prevented by SERMs, because 30-40% of the tumors are ER-negative. Other receptors for retinoids, vitamin D analogs and peroxisome proliferator-activiator, along with transcription factors such as AP-1, NF-kappaB, and STATs (signal transducers and activators of transcription) affect breast tumorigenesis. This is also true for the signal transduction pathways, for example cyclooxygenase 2 (Cox-2), HER2/neu, mitogen-activated protein kinase (MAPK), and PI3K/Akt. Therefore, proteins in pathways that are altered during the process of mammary tumorigenesis may be promising targets of future chemopreventive drugs. Many newly-developed synthetic or natural compounds/agents are now under testing in preclinical studies and clinical trials. Receptor selective retinoids, receptor tyrosine kinase inhibitors (TKIs), SERMs, Cox-2 inhibitors, and others are some of the promising novel agents for the prevention of breast cancer. The chemopreventive activity of these agents and other novel signal transduction inhibitors are discussed in this chapter.

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    Article: The Role of Master Regulators in the Metabolic/ Transcriptional Coupling in Breast Carcinomas
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    Article: The role of master regulators in the metabolic/transcriptional coupling in breast carcinomas.
    Karol Baca-López, Miguel Mayorga, Alfredo Hidalgo-Miranda, Nora Gutiérrez-Nájera, Enrique Hernández-Lemus
    [show abstract] [hide abstract]
    ABSTRACT: Metabolic transformations have been reported as involved in neoplasms survival. This suggests a role of metabolic pathways as potential cancer pharmacological targets. Modulating tumor's energy production pathways may become a substantial research area for cancer treatment. The significant role of metabolic deregulation as inducing transcriptional instabilities and consequently whole-system failure, is thus of foremost importance. By using a data integration approach that combines experimental evidence for high-throughput genome wide gene expression, a non-equilibrium thermodynamics analysis, nonlinear correlation networks as well as database mining, we were able to outline the role that transcription factors MEF2C and MNDA may have as main master regulators in primary breast cancer phenomenology, as well as the possible interrelationship between malignancy and metabolic dysfunction. The present findings are supported by the analysis of 1191 whole genome gene expression experiments, as well as probabilistic inference of gene regulatory networks, and non-equilibrium thermodynamics of such data. Other evidence sources include pathway enrichment and gene set enrichment analyses, as well as motif comparison with a comprehensive gene regulatory network (of homologue genes) in Arabidopsis thaliana. Our key finding is that the non-equilibrium free energies provide a realistic description of transcription factor activation that when supplemented with gene regulatory networks made us able to find deregulated pathways. These analyses also suggest a novel potential role of transcription factor energetics at the onset of primary tumor development. Results are important in the molecular systems biology of cancer field, since deregulation and coupling mechanisms between metabolic activity and transcriptional regulation can be better understood by taking into account the way that master regulators respond to physicochemical constraints imposed by different phenotypic conditions.
    PLoS ONE 01/2012; 7(8):e42678. · 4.09 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

abnormal amplification
 
breast cancer development
 
breast cancer incidence
 
breast tumorigenesis
 
cancer preventive therapy
 
clinical trials
 
cyclooxygenase 2
 
estrogen receptor
 
future chemopreventive drugs
 
growth signals
 
mammary gland tumorigenesis
 
mammary tumorigenesis
 
Multiple alterations
 
newly-developed synthetic
 
novel signal transduction inhibitors
 
promising novel agents
 
Receptor selective retinoids
 
signal transducers
 
signal transduction pathways
 
tumor suppressor genes