The University of Chicago Research Funding

• Principal Investigator: Suzanne Daniela Conzen, MD, Associate Professor, Department of Medicine, Section of Hematology/Oncology, Committee on Cancer Biology, Committee on Molecular Medicine/MPMM, Committee on Molecular Metabolism and Nutrition
• Start Date: June 1, 2009
• Total Award Amount: $19,085

Public Health Relevance

The completion of these aims is expected to advance our understanding of anti-apoptotic signaling and therapy-resistance in epithelial cancers.

Project Description

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.

This award is funded under the American Recovery and Reinvestment Act of 2009, NIH Award number: 3R01CA089208-07S1