Improving breast cancer cure rates will require a detailed molecular understanding of the anti-apoptotic mechanisms used by cancer cells to resist both chemotherapy and """"""""targeted"""""""" treatments. Our laboratory has uncovered a novel anti-apoptotic signaling pathway in breast cancer that is initiated glucocorticoid receptor (GR) activation. Because glucocorticoids are physiological stress-induced hormones and the GR is ubiquitously expressed in breast epithelium, identifying the underlying mechanisms of GR-mediated epithelial cell survival has important implications for advancing our knowledge of both cancer etiology and resistance to therapy. Currently, relatively little is known about the downstream events underlying GR- mediated anti-apoptotic signaling in human mammary epithelial cells (hMECs). Our laboratory has used large-scale microarray and bioinformatic analyses to characterize dynamic gene expression changes over 24 hours following GR activation in hMECs. Through these studies, we have identified MAP kinase phosphatase-1 (MKP-1) and serum and glucocorticoid inducible kinase-1 (SGK-1) as early transcriptional targets of the GR, and we have recently demonstrated the requirement for SGK-1 and MKP-1 activity in GR- mediated survival signaling. SGK-1 and MKP-1, via their potent kinase and phosphatase activities, in turn can regulate the activity of the transcription factors ELK-1 and FOXOSa. We hypothesize that GR-mediated induction of MKP-1 and SGK-1 alters ELK-1 and FOXOSa transcriptional activity, respectively, in turn causing key changes in anti-apoptotic gene expression. In this renewal application, we propose to continue these studies by identifying the specific mechanisms downstream of MKP-1 and SGK-1 induction that contribute to cell survival.
In Aim 1, the GR/MKP-1/ELK-1 pathway will be defined by first validating the ELK- 1 putative targets (identified from gene expression studies) and then examining the role of these targets in GR-mediated cell survival. In parallel, Aim 2 will examine the GR/SGK-1/ FOXOSa pathway. In addition, the possible molecular """"""""cross-talk"""""""" between these two pathways will be investigated.
In Aim 3, a breast cancer xenograft model will be used to determine the in vivo role of SGK-1 and MKP-1 activity in anti-apoptotic signaling, gene expression and resistance to chemotherapy. The completion of these aims is expected to advance our understanding of anti-apoptotic signaling and therapy-resistance in epithelial cancers.
|West, Diana C; Kocherginsky, Masha; Tonsing-Carter, Eva Y et al. (2018) Discovery of a Glucocorticoid Receptor (GR) Activity Signature Using Selective GR Antagonism in ER-Negative Breast Cancer. Clin Cancer Res 24:3433-3446|
|Veneris, Jennifer Taylor; Darcy, Kathleen M; Mhawech-Fauceglia, Paulette et al. (2017) High glucocorticoid receptor expression predicts short progression-free survival in ovarian cancer. Gynecol Oncol 146:153-160|
|Kach, Jacob; Long, Tiha M; Selman, Phillip et al. (2017) Selective Glucocorticoid Receptor Modulators (SGRMs) Delay Castrate-Resistant Prostate Cancer Growth. Mol Cancer Ther 16:1680-1692|
|Conzen, Suzanne D (2017) Recent advances in understanding glucocorticoid receptor function in cancer. Clin Adv Hematol Oncol 15:338-340|
|Tangen, Ingvild L; Veneris, Jennifer Taylor; Halle, Mari K et al. (2017) Expression of glucocorticoid receptor is associated with aggressive primary endometrial cancer and increases from primary to metastatic lesions. Gynecol Oncol 147:672-677|
|Nanda, Rita; Stringer-Reasor, Erica M; Saha, Poornima et al. (2016) A randomized phase I trial of nanoparticle albumin-bound paclitaxel with or without mifepristone for advanced breast cancer. Springerplus 5:947|
|West, Diana C; Pan, Deng; Tonsing-Carter, Eva Y et al. (2016) GR and ER Coactivation Alters the Expression of Differentiation Genes and Associates with Improved ER+ Breast Cancer Outcome. Mol Cancer Res 14:707-19|
|Agyeman, Abena S; Jun, Wesley J; Proia, David A et al. (2016) Hsp90 Inhibition Results in Glucocorticoid Receptor Degradation in Association with Increased Sensitivity to Paclitaxel in Triple-Negative Breast Cancer. Horm Cancer 7:114-26|
|Singh, Puneet; Brock, Clifton O; Volden, Paul A et al. (2015) Glucocorticoid receptor ChIP-sequencing of subcutaneous fat reveals modulation of inflammatory pathways. Obesity (Silver Spring) 23:2286-93|
|Fan, Xiaobing; Macleod, Kay; Mustafi, Devkumar et al. (2015) Correlation of In Vivo and Ex Vivo ADC and T2 of In Situ and Invasive Murine Mammary Cancers. PLoS One 10:e0129212|
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