Figure 11.

The melding of model systems. During the past 25 years, the MCF-7 breast cancer cell line has been used to recapitulate an evolving model in vivo of acquired tamoxifen resistance (62) observed in clinical breast cancer. In parallel, the same cell line has been used to recapitulate models in vitro of estrogen deprivation using either fulvestrant, that destroys the ER protein, or aromatase inhibitors that create a long-term estrogen-deprived state. The cells derived from estrogen deprivation with fulvestrant loose the ER (90), but estrogen deprivation in an estrogen-free environment in vitro increases the ER level. Clones grow out that are sensitive to estrogen-induced apoptosis (86). A c-Src inhibitor blocks estrogen-induced apoptosis in the short-term (94), but long-term (2 months) treatment with estrogen plus a c-Src inhibitor results in a new populations of cells (MCF-7:PF) (96) that recapitulates in vitro Phase I resistance to SERMs in vivo. These data, accumulated over decades, illustrate the plasticity of cell populations in that successful attempt to adapt to hostile environment. Reproduced with permission from (206).