A key issue for tumor biology is to understand the mechanisms controlling tumor heterogeneity, and to determine the extent of tumor heterogeneity that will affect the clinical outcome. In a recent study published on Nature, Professor Cédric Blanpain, leader of the research team of Brussels University, in collaboration with Australia’s Wayne Phillips and Christos Sotiriou from Belgium Bordet Institute, found the origins of the PIK3CA gene induced breast tumor cells and showed that the origin of the tumor cells controls tumor heterogeneity and are associated with different types of breast cancer and prognosis.
Breast cancer is the most common cancer in women. According to histological and molecular features, human breast cancer can be divided into different subtypes, including luminal tumors, ERBB2 tumors and basal-like tumors. PIK3CA gene and p53 (also known as TP53) are the two most common mutated genes associated with different molecular subtypes. In this new study, Alexandra Van Keymeulen and his colleagues, used the most advanced genetic mouse models to define the cellular origin of Pik3ca-derived tumors and the impact of mutations in this gene on tumor heterogeneity.
They found that it depends on the cells of origin, and PIK3CA and p53 can cause very different types of tumors. Luminal cells often lead to more aggressive tumors. The First author Alexandra Van Keymeulen commented that, they were surprised by the basal cells of the oncogene Pik3ca, which can induce the formation of the luminal tumors, and its expression in luminal cells will lead to heterogeneity and more aggressive tumors, including basal-like tumors.
By analyzing the early tumor formation steps, Alexandra Van Keymeulen and his colleagues found that the oncogenes Pik3ca expression can activate a multi-directional differentiation programming, similar to an immature embryonic state of adult stem cells. By the expression of oncogenes PIK3CA and the molecular characteristics undergoing cell fate transition, it shows us the profound, oncogene-induced reprogramming newly formed cells, and determines the gene expression profiles and the switching characteristics of different cell fate, which helps us to predict the origin of cancer cells, tumor type and clinical outcome in breast cancer patients .
The author Cédric Blanpain also commented that, these new findings not only demonstrate the importance of the origin of cancer control for the heterogeneity of breast cancer, but also indicate that gene expression profiles in tumor early stages can predict the type of breast cancers that will eventually develop into.
In short, this new study identifies the cellular origin of Pik3ca-induced tumours and reveals that oncogenic Pik3caH1047R activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumour initiation, thus helping to set the stage for future intratumoural heterogeneity. These findings also have great importance for our understanding of the mechanisms controlling tumour heterogeneity and the development of new strategies to block PIK3CA breast cancer initiation.
Source: Reactivation of multipotency by oncogenic PIK3CA induces breast tumour heterogeneity, Nature (2015) doi:10.1038/nature14665.