Affiliation: INSERM UMR S 893, Hopital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75571, Paris Cedex,France.
A majority of breast cancers (BC) display characteristics of epithelial cells and express estrogen receptors and/or HER-2 (a member of the epidermal growth factor receptor family). About one-fifth of BC is constituted of basal cells for which there is no specific category of proliferation regulators. Insulin-like growth factor (IGF) signaling is involved in most BC cells, irrespective of cell type. All inducers of cell proliferation employ transcriptional as well as non-transcriptional mechanisms to activate the cascade of cyclindependent kinases, which causes irreversible progression to the G1/S phase transition. We analyze the pathways of the different inducers that lead to this cascade. Several actors in the mitogenic signal transduction are required irrespective of the initial signal although their functions may differ: for example members of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3K) cascades. As some of these proteins are also involved in the cell survival mechanisms, they appear to be good targets for therapeutic intervention. In the case of the estrogen-dependent cells, complex interplay between the estrogen receptor (a conditional transcription factor), co-repressors and co-activators offers additional molecular targets for therapy. Besides, we have found that p21WAF1, an inhibitor of cyclin-dependent kinases, can orient the cell to either proliferation or differentiation suggesting that at an early stage of BC development it may be possible to reverse the cellular changes associated with malignant transformation.