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Accumulating preclinical and clinical evidence supports a pro-oncogenic function for Notch signaling in several solid tumors, particularly but not exclusively in breast cancer. Notch inhibitory agents, such as γ-secretase inhibitors, are being investigated as candidate cancer therapeutic agents. Interest in therapeutic modulation of the Notch pathway has been increased by recent reports, indicating that its role is important in controlling the fate of putative ‘breast cancer stem cells’. However, as is the case for most targeted therapies, successful targeting of Notch signaling in cancer will require a considerable refinement of our understanding of the regulation of this pathway and its effects in both normal and cancer cells. Notch signaling has bidirectional ‘cross talk’ interaction with multiple other pathways that include candidate therapeutic targets. Understanding these interactions will greatly increase our ability to design rational combination regimens. To determine which patients are most likely to benefit from treatment with Notch inhibitors, it will be necessary to develop molecular tests to accurately measure pathway activity in specific tumors. Finally, mechanism-based toxicities will have to be addressed by a careful choice of therapeutic agents, combinations and regimens. This article summarizes the current state of the field, and briefly describes opportunities and challenges for Notch-targeted therapies in oncology.Oncogene (2008) 27, 5124–5131; doi:10.1038/onc.2008.226 [ABSTRACT FROM AUTHOR]

Abstract: Estrogen suppression through the use of an aromatase inhibitor is an effective endocrine treatment option for postmenopausal breast cancer patients with estrogen receptor (ER)-positive disease, however, there are concerns that long-term estrogen deprivation will inevitably lead to resistance. To address the issue of acquired resistance to long-term estrogen deprivation our laboratory has developed an ER+/PR− hormone-independent breast cancer cell line, MCF-7:5C which is a variant clone of wild-type MCF-7 cells. Originally, these cells were cultured in estrogen-free MEM containing 5% charcoal-stripped calf serum and were found to be resistant to both estradiol (E2) and antiestrogens. Interestingly, a completely different phenomenon was observed when MCF-7:5C cells were cultured in phenol red-free RPMI 1640 medium containing 10% charcoal-stripped fetal bovine serum (SFS). Using DNA quantitation assays, we examined the effect of E2 on the growth of MCF-7:5C cells under different media conditions. Our results showed that 10−9 M E2 caused a dramatic 90% reduction in the growth of MCF-7:5C cells cultured in RPMI medium containing 10% SFS but did not have any significant inhibitory effects on cells cultured in MEM media. Additional experiments were performed to determine whether the medium or the serum facilitated the inhibitory effects of E2 and the results indicated that it was the serum. Annexin V and DAPI staining confirmed that the E2-induced growth inhibition of MCF-7:5C cells was due to apoptosis. We also examined the tumorigenic potential of MCF-7:5C cells by injecting 1×107 cells/site into ovariectomized athymic mice and found that these cells, previously cultured in RPMI media, spontaneously grew into tumors in the absence of E2. Overall, these results show that low concentrations (>10−11 M) of E2 are capable of inducing apoptosis in an aromatase resistant breast cancer cell model and that this effect is highly influenced by the medium in which the cells are grown. [Copyright &y& Elsevier]