Abstract SY27-03: Breast cancer stem cell state transitions mediate therapeutic resistance

Tumor cellular heterogeneity represents one of the greatest challenges to the development of molecular targeted therapeutics. A component of this heterogeneity is generated through stochastic mutation and subsequent clonal selection. However, in addition to genetic mechanisms, there is increasing evidence for a role of epigenetic regulation in generating cellular heterogeneity and therapeutic resistance. Epigenetic regulation of gene expression occurs during normal cellular differentiation and during carcinogenesis generates tumors that display a hierarchical organization. At the apex of this hierarchy are “cancer stem cells” (CSCs) that are characterized by their ability to self-renew, as well as to generate the populations constituting the tumor bulk. CSCs mediate tumor metastasis as well as resistance to cytotoxic chemotherapy and radiation therapy. A number of molecular mechanisms accounting for therapeutic resistance of CSCs have been described, including altered cell cycle kinetics, increased DNA repair, antioxidant defense, expression of antiapoptotic proteins, expression of cellular transporters and chemotherapy metabolizing enzymes.Despite the fact that CSCs and more differentiated progeny derived from these cells share the same mutation profiles, they may be driven by and depend upon different signal transduction pathways. As a result, therapies capable of targeting differentiated cells may be ineffective at eliminating CSC populations. For example, the BCR-abl ...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Tumor Biology Source Type: research