Breast cancer gene therapy

Breast cancer is one of the major health threats for women all over the world. It is the most commonly diagnosed cancer in women and the second leading cause of cancer death in women in Western society (unpublished data from the Comprehensive Cancer Monitoring Program Meeting in Europe, 2003). In recent years, the mortality rate of breast cancer has declined slightly [80], thanks to early detection programs and the advances in therapy, and especially improvements in systemic therapy, such as new chemotherapeutic agents and aromatase inhibitors. However, even localized diseases will relapse locally or distantly in a significant proportion of patients. When disease progresses to the metastatic stage it becomes essentially incurable and the median survival time is about 2 years. Chemotherapy is the main treatment at this stage. The response rate of combined chemotherapies ranges from 35% to 67%, and the median response duration is short, usually approximately 9 months [6]. Therefore, finding alternative therapies for patients whose disease is refractory to chemotherapy or hormone therapy is critical. Gene therapy is one of the alternative therapies. Cancer is a genetic disease. Almost all types of cancers exhibit genomic instability [92, 121, 149]. Cancer may arise as a result of hereditary or acquired somatic mutations. These genetic alternations may occur as changes in a single or a cluster of nucleotides, microsatellite instability, loss or gain of whole genes, changes in chromosomal structures, or even complete loss of a chromosome. The consequences of genetic changes leads to loss of tumor suppressive function, to oncogenicity, or to activation or inactivation of those genes whose products regulate genomic stability. Familial clustered breast cancers are found in only 10% of all breast cancers cases. In this group, hereditary breast cancers occur in some syndromes. Although hereditary breast cancers are highly penetrative and are associated with definitive genetic changes, such as BRCA1, BRCA2, and p53, the estimated incidence of these breast cancers is only about 20% in patients with familial clustered breast cancer. The majority of other cases of familial clustered breast cancer and sporadic cases result from the accumulation of multiple somatic genetic changes interacting with environmental factors. Once a key mutated gene or a dysregulated signaling pathway is identified in cancers, conceptually we can transfer a therapeutic gene to cancer cells, reversing the malignant phenotype by correcting its genetic defects, blocking the abnormal signaling, or inducing the death of cancer cells specifically. Such treatment, known as gene therapy, is the most straightforward, effective treatment for cancer. In recent years, advances in the technology of gene transfer have made gene therapy feasible for cancer treatment. The gene therapy system is composed of DNA that contains the therapeutic gene and a biological or synthetic vector that can be complexed with DNA and carries the DNA to cancer cells, releasing it inside the cells. In this chapter, we will discuss the principles of gene therapy, including delivery systems, therapeutic targets, in vitro and preclinical experiments, and ongoing clinical trials of breast cancer gene therapy. © Springer-Verlag Berlin Heidelberg 2006.