1. Stress Signaling in Breast Cancer:
The PI3-K/SGK-1 Pathway
Larissa Belova, Ph.D.
Biomedical Sciences Cluster Retreat
Lake Lawn Resort, Delavan,WI
April 27, 2007

2. The PI3-K/SGK-1 pathway is an emerging player in
understanding cancer cell survival
Glucocorticoid, UV,
osmotic and heat
shock, free radicals
RTK
RTK
PIP2
PI3-K PDK1 AKT
PIP3 P P
GR GRGR
PDK1
Nucleus
Transcription SGK-1
Transcription SGK-1
factors P P CELL SURVIVAL
P P
GR (Foxo3a)
GR SGK-1 SGK-1
GRE SGK-1
DEGRADATION

3. SGK-1: why do we care?
SGK-1 provides a potent survival signal in breast cancer cells (Wu et. al, Cancer Res. 2004)

4. Tonight’s talk:
• Hsp90 plays a key role in regulation of SGK-
1 phosphorylation and activity
• The E3 ligase CHIP plays a role in ubiquitin
modification and proteasome-mediated
degradation of SGK-1

5. SGK-1 forms a complex with Hsp90

6. Inhibition of Hsp90 function is associated with
dephosphorylation and inactivation of SGK-1

7. Hsp90 activity is associated with
SGK-1 phosphorylation downstream
of PI3-kinase

8. SGK-1 is inactivated and AKT is
activated following Hsp90 inhibition

9. • The E3 ligase CHIP plays a role in ubiquitin
modification and proteasome-mediated
degradation of SGK-1

10. E3 ligase CHIP binds and ubiquitinates
SGK-1

11. SGK-1 and CHIP expression in human breast tissues
SGK-1 positively
expressed in
• Normal
epithelium - 36%
• DCIS - 63%
• IDC - 54%
• Metastatic
tumors - 62%
CHIP positively
expressed in
• Normal
epithelium - 87%
• DCIS - 99%
• IDC - 97%
• Metastatic
tumors - 100%
SGK-1 expressed 56% in tumors (DCIS, IDC, metastatic, n=326) and
36% in normal epithelium (P<0.001)

12. CHIP and SGK-1 expression are inversely correlated in
normal versus malignant epithelium
In CHIP-positive samples, SGK-1 is less expressed in normal
epithelium (42%) but more in tumors (58%) (P=0.012)

13. Glucocorticoid, UV,
osmotic and heat
shock, free radicals
ErbB2
RTK
RTK
PIP2
PI3-K PDK1 AKT
P P
PIP3
GR GR GR
PTEN
?
Hsp70
CHIP
Nucleus
SGK-1 Hsp90 SGK-1
SGK-1 CELL SURVIVAL
Transcription Transcription P
factors
P P P P
P E2 (Foxo3a)
GR
GR SGK-1 Hsp90
SGK-1 Hsp90 Ubiquitin
DEGRADATION

14. Acknowledgements
Dr. Conzen Dr. O.I. Olopade M. Kocherginsky
D. R. Brickley A. Khramtsov
B. Delgado
B.Ky
S.K. Sharma