PMID- 12554765
OWN - NLM
STAT- MEDLINE
DCOM- 20040226
LR  - 20220317
IS  - 0888-8809 (Print)
IS  - 0888-8809 (Linking)
VI  - 17
IP  - 4
DP  - 2003 Apr
TI  - Insulin-like growth factor-I inhibits progesterone receptor expression in breast 
      cancer cells via the phosphatidylinositol 3-kinase/Akt/mammalian target of 
      rapamycin pathway: progesterone receptor as a potential indicator of growth 
      factor activity in breast cancer.
PG  - 575-88
AB  - Although interactions between estrogen and growth factor signaling pathways have 
      been studied extensively, how growth factors and progesterone regulate each other 
      is less clear. In this study, we found that IGF-I sharply lowers progesterone 
      receptor (PR) mRNA and protein levels in breast cancer cells. Other growth 
      factors, such as epidermal growth factor, also showed the same effect. The 
      decrease of PR levels was associated with reduced PR activity. Unlike progestins, 
      IGF-I does not utilize the proteasome for down-regulating PR. Instead, the 
      IGF-I-mediated decrease in PR levels is via an inhibition of PR gene 
      transcription. In addition, the phosphatidylinositol 3-kinase 
      (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway was found to be 
      specifically involved in this IGF-I effect. Our data also suggest that the IGF-I 
      down-regulation of PR is not mediated via a reduction of estrogen receptor (ER) 
      levels or activity. First, IGF-I induced ligand-independent ER activity while 
      reducing ER-dependent PR levels. Second, whereas PR and cyclin D1 are both ER 
      up-regulated, IGF-I increased cyclin D1 levels while decreasing PR levels. Third, 
      constitutively active PI3K or Akt induced ER activity but reduced PR levels and 
      activity. Taken together, our data indicate that IGF-I inhibits PR expression in 
      breast cancer cells via the PI3K/Akt/mTOR pathway. Because low or absent PR in 
      primary breast cancer is associated with poor prognosis and response to hormone 
      therapy, our results suggest that low PR status may serve as an indicator of 
      activated growth factor signaling in breast tumor cells, and therefore of an 
      aggressive tumor phenotype and resistance against hormonal therapy.
FAU - Cui, Xiaojiang
AU  - Cui X
AD  - Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 
      77030, USA.
FAU - Zhang, Ping
AU  - Zhang P
FAU - Deng, Wanleng
AU  - Deng W
FAU - Oesterreich, Steffi
AU  - Oesterreich S
FAU - Lu, Yiling
AU  - Lu Y
FAU - Mills, Gordon B
AU  - Mills GB
FAU - Lee, Adrian V
AU  - Lee AV
LA  - eng
GR  - R01CA94118/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20030102
PL  - United States
TA  - Mol Endocrinol
JT  - Molecular endocrinology (Baltimore, Md.)
JID - 8801431
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Growth Substances)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Receptors, Estrogen)
RN  - 0 (Receptors, Progesterone)
RN  - 136601-57-5 (Cyclin D1)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (AKT1 protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
EIN - Mol Endocrinol. 2003 Sep;17(9):1892
MH  - Breast Neoplasms/drug therapy/*metabolism
MH  - Cyclin D1/drug effects/metabolism
MH  - Enzyme Inhibitors/pharmacology
MH  - Female
MH  - Growth Substances/metabolism/pharmacology
MH  - Humans
MH  - Insulin-Like Growth Factor I/*metabolism/pharmacology
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Predictive Value of Tests
MH  - Protein Kinases/genetics/metabolism
MH  - *Protein Serine-Threonine Kinases
MH  - Proto-Oncogene Proteins/antagonists & inhibitors/*metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - Receptors, Estrogen/drug effects/metabolism
MH  - Receptors, Progesterone/drug effects/genetics/*metabolism
MH  - Signal Transduction
MH  - Sirolimus/*metabolism
MH  - TOR Serine-Threonine Kinases
MH  - Transcription, Genetic
MH  - Tumor Cells, Cultured
EDAT- 2003/01/30 04:00
MHDA- 2004/02/27 05:00
CRDT- 2003/01/30 04:00
PHST- 2003/01/30 04:00 [pubmed]
PHST- 2004/02/27 05:00 [medline]
PHST- 2003/01/30 04:00 [entrez]
AID - me.2002-0318 [pii]
AID - 10.1210/me.2002-0318 [doi]
PST - ppublish
SO  - Mol Endocrinol. 2003 Apr;17(4):575-88. doi: 10.1210/me.2002-0318. Epub 2003 Jan 
      2.