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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA089208-08
Application #
7798228
Study Section
Special Emphasis Panel (ZRG1-ONC-Q (01))
Program Officer
Sathyamoorthy, Neeraja
Project Start
2000-12-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
8
Fiscal Year
2010
Total Cost
$226,927
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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