The multi-hit hypothesis in basal-like breast cancer

Abstract

It has been known for many years that for a "normal" un-transformed cell to become immortal and subsequently tumorigenic requires multiple pro-oncogenic changes in the levels of protein expression and function. Genes most commonly associated with the process of oncogenesis include: p53 inactivating mutation; hDM2 overexpression; p16 reduced expression; K-/H-RAS activating mutation; PTEN inactivating mutation/deletion; EGFR activating mutation and overexpression; retinoblastoma inactivating mutation and deletion; Cyclin proteins overexpression; CD95 reduced expression; protective BCL-2 proteins overexpression; to name but just a few of such molecules.1-5 That the minimally required specific proteins for oncogenesis are not known for many specific tumor types remains a challenge for the rational design of molecular targeted therapies.

Modelling genotypes in their microenvironment to predict single- and multi-cellular behaviour

“…Importantly, cooccurring mutations show a significantly more aggressive phenotype with faster growth ( Figure 2C) with respect to cases in which single mutations occur ( Figure 2D, and Figure S3A). This is in agreement with experimental data showing that co-existing alterations in these specific genes in pre-malignant breast cancer cell lines significantly increases growth with respect to the single alterations in EGFR, P53 and PTEN genes (30,31). Furthermore, we confirm that the presence of active growth factor signalling is determinant for rapid growth.…”

Modeling genotypes in their microenvironment to predict single- and multi-cellular behavior

“…This model has been shown to express markers that are associated with the basal-epithelial phenotype, but it does not carry the mutations frequently observed in this breast cancer type. In these cells, the effect of PTEN deletion, p53 loss-of-function mutation, and EGFR activating mutations on growth and colony formation has been previously measured under conditions of starvation [ 34 , 35 ]. As shown by Pires et al [ 35 ], these mutations as individual oncogenes could not stimulate growth in 3D culture in soft agar, while the double mutants showed increased growth, and the triple mutant grew significantly more rapidly and formed significantly more colonies than either of the matched double mutants.…”