ABSTRACT
Most breast cancer deaths occur in women with recurrent, estrogen receptor (ER)-α(+), metastatic tumors. There is a critical need for therapeutic approaches that include novel, targetable mechanism-based strategies by which ERα (+) tumors can be resensitized to endocrine therapies. The objective of this study was to validate a group of nuclear transport genes as potential biomarkers to predict the risk of endocrine therapy failure and to evaluate the inhibition of XPO1, one of these genes as a novel means to enhance the effectiveness of endocrine therapies. Using advanced statistical methods, we found that expression levels of several of nuclear transport genes including XPO1 were associated with poor survival and predicted recurrence of tamoxifen-treated breast tumors in human breast cancer gene expression data sets. In mechanistic studies we showed that the expression of XPO1 determined the cellular localization of the key signaling proteins and the response to tamoxifen. We demonstrated that combined targeting of XPO1 and ERα in several tamoxifen-resistant cell lines and tumor xenografts with the XPO1 inhibitor, Selinexor, and tamoxifen restored tamoxifen sensitivity and prevented recurrence in vivo. The nuclear transport pathways have not previously been implicated in the development of endocrine resistance, and given the need for better strategies for selecting patients to receive endocrine modulatory reagents and improving therapy response of relapsed ERα(+) tumors, our findings show great promise for uncovering the role these pathways play in reducing cancer recurrences.
Subject(s)
Antineoplastic Agents, Hormonal/pharmacology , Estrogen Receptor alpha/metabolism , Karyopherins/metabolism , Mitogen-Activated Protein Kinase 7/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Tamoxifen/pharmacology , Animals , Biological Transport/drug effects , Biological Transport/genetics , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Line, Tumor , Cell Nucleus/drug effects , Cell Nucleus/genetics , Cell Nucleus/metabolism , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Estrogen Receptor alpha/genetics , Female , Gene Expression Regulation, Neoplastic/drug effects , Gene Expression Regulation, Neoplastic/genetics , Humans , Karyopherins/genetics , MCF-7 Cells , Mice , Mice, Inbred BALB C , Mice, Nude , Mitogen-Activated Protein Kinase 7/genetics , Receptors, Cytoplasmic and Nuclear/genetics , Signal Transduction/drug effects , Signal Transduction/genetics , Exportin 1 ProteinABSTRACT
Estrogens regulate function of reproductive and non-reproductive tissues in healthy and diseased states including breast cancer. They mainly work through estrogen receptor alpha (ERα) and/or estrogen receptor beta (ERß). There are various ERα targeting agents that have been used for treatment of ER (+) breast tumors. The impact of direct nuclear activity of ER is very well characterized in ER (+) breast cancers and development and progression of endocrine resistance. Recent studies also suggested important roles for extranuclear-initiated ERα pathways, which would decrease the potency and efficiency of ERα targeting agents. In this mini-review, we will discuss the role of nuclear and extra-nuclear ER signaling and how they relate to therapy resistance in breast cancer.
