TY - JOUR
T1 - Reciprocal Feedback Regulation of PI3K and Androgen Receptor Signaling in PTEN-Deficient Prostate Cancer
AU - Carver, Brett S.
AU - Chapinski, Caren
AU - Wongvipat, John
AU - Hieronymus, Haley
AU - Chen, Yu
AU - Chandarlapaty, Sarat
AU - Arora, Vivek K.
AU - Le, Carl
AU - Koutcher, Jason
AU - Scher, Howard
AU - Scardino, Peter T.
AU - Rosen, Neal
AU - Sawyers, Charles L.
N1 - Funding Information:
The authors would like to thank M. Isaka and the Genetically Engineered Mouse Facility for maintaining our mouse colonies. We would like to thank P.P. Pandolfi for providing the Pten lox/lox PB- Cre GEM model. A special thanks to all members of the Sawyers' lab and the Rosen lab for providing informative discussion. This work was funded in part through: NIH Prostate SPORE P50-CA92629; NIH Small-Animal Imaging Research Program (SAIRP) R24 CA83084; and NIH Center Grant P30 CA08748. B.S.C. has a Prostate Cancer Foundation Young Investigator Award and STARR Cancer Consortium Award. C.L.S. is a Howard Hughes Medical Institute Investigator. B.S.C. and C.L.S. designed the study; B.S.C., J.W., and C.C. performed the mouse experiments. B.S.C., C.C., and V.K.A. performed the in vitro experiments. H.H. and Y.C. performed the expression array analyses in human and mouse prostate cancers, respectively. S.C. and N.R. provided expert guidance in defining the mechanism of PI3K feedback inhibition on AR. J.K. and C.L. conducted the animal MRI experiments. P.T.S. and H.S. provided valuable discussion with regard to clinical correlates. B.S.C. and C.L.S. prepared the manuscript. All authors approved of the final manuscript. C.L.S. is a co-inventor of MDV3100 and owns stock in Medivation.
PY - 2011/5/17
Y1 - 2011/5/17
N2 - Prostate cancer is characterized by its dependence on androgen receptor (AR) and frequent activation of PI3K signaling. We find that AR transcriptional output is decreased in human and murine tumors with PTEN deletion and that PI3K pathway inhibition activates AR signaling by relieving feedback inhibition of HER kinases. Similarly, AR inhibition activates AKT signaling by reducing levels of the AKT phosphatase PHLPP. Thus, these two oncogenic pathways cross-regulate each other by reciprocal feedback. Inhibition of one activates the other, thereby maintaining tumor cell survival. However, combined pharmacologic inhibition of PI3K and AR signaling caused near-complete prostate cancer regressions in a Pten-deficient murine prostate cancer model and in human prostate cancer xenografts, indicating that both pathways coordinately support survival.
AB - Prostate cancer is characterized by its dependence on androgen receptor (AR) and frequent activation of PI3K signaling. We find that AR transcriptional output is decreased in human and murine tumors with PTEN deletion and that PI3K pathway inhibition activates AR signaling by relieving feedback inhibition of HER kinases. Similarly, AR inhibition activates AKT signaling by reducing levels of the AKT phosphatase PHLPP. Thus, these two oncogenic pathways cross-regulate each other by reciprocal feedback. Inhibition of one activates the other, thereby maintaining tumor cell survival. However, combined pharmacologic inhibition of PI3K and AR signaling caused near-complete prostate cancer regressions in a Pten-deficient murine prostate cancer model and in human prostate cancer xenografts, indicating that both pathways coordinately support survival.
UR - http://www.scopus.com/inward/record.url?scp=79955975429&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2011.04.008
DO - 10.1016/j.ccr.2011.04.008
M3 - Article
C2 - 21575859
AN - SCOPUS:79955975429
SN - 1535-6108
VL - 19
SP - 575
EP - 586
JO - Cancer Cell
JF - Cancer Cell
IS - 5
ER -