The Role of Mutant PIK3CA and TP53 in Human Breast Carcinogenesis

Abstract

Breast cancer is the second leading cause of cancer-associated deaths among women in the United States, with greater than 40,000 women dying each year from this disease. While specific DNA mutations have been shown to be involved in the development of breast cancer, it is the cooperation and collaborative effects of multiple mutations and genetic alterations that leads to carcinogenesis. The accumulation of mutations suggests that accurate models cannot focus on a single mutation but rather the interplay of several mutations. Thus, it has becoming increasingly apparent that the successful treatment of breast cancer will rely upon understanding how multiple pathogenic mutations and pathways interact. Each year, approximately 11,000 new cases of breast cancer will harbor both a TP53 and PIK3CA mutation, the two most common somatic mutations in nonhereditary breast cancer. The implementation of gene targeting to develop a panel of somatic knock-in isogenic cell lines harboring both a PIK3CA and a TP53 mutation in human breast epithelial cells provides a model with multiple pathogenic mutations. The model more accurately demonstrates the progressive genetic events leading to breast carcinogenesis. The development of a closely related panel of isogenic cell lines will all phenotypic transformations to be attributed to dysregulation of an entire pathway, a specific mutation, or a clonal variation. Furthermore it allows for the identification of potential therapeutic biomarkers, targets, and provides new mechanistic insight between the two most somatically mutated pathways in breast cancer.