Pin1 as a Biomarker of ER+ Breast Cancers to Predict the Response to Tamoxifen and mTOR Inhibitors
Annual summary rept. 1 Apr 2008-31 Mar 2009
DUKE UNIV DURHAM NC
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Preliminary data from our lab showed that immortalized Pin1 null mouse embryo fibroblasts MEFs had decreased S6K phosphorylation and increased Akt phosphorylation. Since Akt and S6K activity have been shown to influence the sensitivity of cells to both Tamoxifen and mTOR inhibitors, we hypothesized that Pin1 could serve as a biomarker to help predict the response of estrogen receptor positive ER breast tumors to these therapies. This preliminary data was not reproducible in primary Pin1 null MEFs. Although Pin1 binds phosphorylated S6K, we found no evidence to support a role for Pin1 in modulating S6K and Akt activity. We did, however, find a modest but reproducible defect in global protein synthesis and G0 exit. To further characterize the in vivo role of Pin1 in protein synthesis and proliferation, we turned our attention to cells of the immune system. Upon LPS challenge, we find a marked defect in the ability of Pin1 null mice to produce many cytokines, including IL-6. This finding has been confirmed in primary Pin1 null MEFs, which also exhibit a defect in LPS-stimulated IL-6 secretion. Future studies will seek to identify the mechanism by which Pin1 regulates IL-6 production. This information will then be applied to breast cancer cells, as IL-6 has been reported to play a role in breast cancer progression and influence the sensitivity of breast cancer cells to chemotherapeutic agents.
- Medicine and Medical Research