Modelling molecular mechanisms of breast cancer and invasion: lessons from the normal gland

Abstract

The interplay between genes and environment is complex, particularly when it comes to cancer. Studies on breast cancer cells have shown that environmental influences dominate over genotype in their effect on phenotype, and can cause cancerous cells to revert to a non-malignant phenotype, while remaining genotypically malignant. Using breast tissue in three-dimensional cell culture has proved a better model than traditional two-dimensional cell culture in that different cell types can be seen to behave differently to the same pro-apoptotic signal, with normal cells surviving.

Figure 1. Formation of model mouse acini in cell culture on a laminin-rich ECM

Similarities can be seen between acini in vivo and in three-dimensional cell culture. Reproduced from [4] with permission.

Figure 2. Schematic diagram showing the effect of laminin on the expression of genes involved in milk production in mammary epithelial cells

Figure based on unpublished work by R. Xu and M.J. Bissell. AcH4, acetylated histone H4; C/EBP, CCAAT/enhancer-binding protein; GR, glucocorticoid receptor; RNA Pol II, RNA polymerase II; STAT5, signal transducer and activator of transcription 5.

Figure 3. Effect of inhibitory antibodies to β1 integrin on malignant breast cells

Inhibition of β1 integrin causes the cells to revert to a normal phenotype although their genotype remains unchanged. Reproduced from The Journal of Cell Biology, 1997, 137:231–245. Copyright 1997 The Rockefeller University Press.

Figure 4. Effects of increased MMP-3 expression on mouse mammary epithelial cells

(a) Increased genomic instability, shown as an increase in the rate of amplification at the CAD locus. FISH, fluorescence in situ hybridization; PALA, partition affinity ligand assay. (b) Cell shape changes caused by MMP-3-induced alterations in the actin cytoskeleton. Reproduced with permission from [13]. © 2005 Nature Publishing Group; http://www.nature.com