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

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.