PMID- 15145521
OWN - NLM
STAT- MEDLINE
DCOM- 20040722
LR  - 20220316
IS  - 0304-3835 (Print)
IS  - 0304-3835 (Linking)
VI  - 209
IP  - 1
DP  - 2004 Jun 8
TI  - Tamoxifen induces the expression of maspin through estrogen receptor-alpha.
PG  - 55-65
AB  - Maspin (mammary serine protease inhibitor) is a tumor suppressor gene that plays 
      an important role in inhibiting tumor growth, invasion and metastasis. Maspin 
      expression is down regulated at transcription level in primary and metastatic 
      breast tumor cells. Previous studies on hormonal regulation of maspin prompt us 
      to test whether an estrogen antagonist tamoxifen (TAM) can exert its anti-tumor 
      function by up regulating maspin gene expression. For this purpose, we first 
      tested whether maspin promoter could be activated in normal and several breast 
      tumor cells. We then carried out a series of promoter analysis in which estrogen 
      receptors and TAM were reconstituted in an in vitro cell culture system. Here we 
      report our new finding that tumor suppresser gene maspin is one of the TAM target 
      genes. TAM induces a maspin/luciferase reporter in cell culture and this 
      induction requires the presence of (estrogen receptor alpha) ERalpha but not 
      estrogen receptor-beta (ERbeta). Maspin promoter deletion and mutation analysis 
      showed that the cis element(s) within a region between -90and+87 bp but not the 
      HRE site (-272 bp) was involved in TAM induction of maspin expression. TAM bound 
      ERalpha may directly control maspin gene expression through the interaction with 
      cofactor (s). Analysis using several ERalpha mutants showed that the N-terminal 
      A/B motif (AF-1) was critical for maspin basal level transcription activation. An 
      ERalpha mutant with point mutations at DNA binding domain abolished estrogen 
      induction of an ERE-luciferase reporter but was still active in activating maspin 
      promoter by TAM. LBD-AF2 domain was required for ERalpha-dependent TAM induction. 
      Deletion of LBD-AF2 or a point mutation in the ERalpha LBD-AF2 region 
      (LBDmtL539A) completely abolished the activation of maspin promoter, suggesting 
      that TAM induction of maspin involves the recruitment of cofactor(s) by ERalpha 
      to the maspin promoter region. This finding indicates that one of the pathways 
      for cancer prevention and tumor inhibition by TAM is mediated through the 
      activation of tumor suppressor gene maspin in breast cancer.
FAU - Liu, Zesheng
AU  - Liu Z
AD  - Department of Molecular and Cellular Biology, Baylor College of Medicine, One 
      Baylor Plaza, Alkek bldg, N630 Houston, TX 77030, USA.
FAU - Shi, Heidi Y
AU  - Shi HY
FAU - Nawaz, Zafar
AU  - Nawaz Z
FAU - Zhang, Ming
AU  - Zhang M
LA  - eng
GR  - CA79736/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - Ireland
TA  - Cancer Lett
JT  - Cancer letters
JID - 7600053
RN  - 0 (Antineoplastic Agents, Hormonal)
RN  - 0 (Estrogen Receptor alpha)
RN  - 0 (Estrogens)
RN  - 0 (Proteins)
RN  - 0 (Receptors, Estrogen)
RN  - 0 (SERPIN-B5)
RN  - 0 (Serpins)
RN  - 094ZI81Y45 (Tamoxifen)
RN  - EC 1.13.12.- (Luciferases)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents, Hormonal/*pharmacology
MH  - COS Cells
MH  - Dose-Response Relationship, Drug
MH  - Estrogen Receptor alpha
MH  - Estrogens/metabolism
MH  - Gene Deletion
MH  - *Gene Expression Regulation, Neoplastic
MH  - Genes, Reporter
MH  - Genes, Tumor Suppressor
MH  - Genetic Vectors
MH  - Humans
MH  - Luciferases/metabolism
MH  - MAP Kinase Signaling System
MH  - Mutation
MH  - Neoplasm Invasiveness
MH  - Neoplasm Metastasis
MH  - Plasmids/metabolism
MH  - Point Mutation
MH  - Promoter Regions, Genetic
MH  - *Protein Biosynthesis
MH  - Protein Structure, Tertiary
MH  - Proteins/genetics
MH  - Receptors, Estrogen/*metabolism
MH  - Serpins/*biosynthesis/genetics
MH  - Signal Transduction
MH  - Tamoxifen/*pharmacology
MH  - Transfection
MH  - Up-Regulation
EDAT- 2004/05/18 05:00
MHDA- 2004/07/23 05:00
CRDT- 2004/05/18 05:00
PHST- 2003/09/21 00:00 [received]
PHST- 2003/11/21 00:00 [revised]
PHST- 2003/11/22 00:00 [accepted]
PHST- 2004/05/18 05:00 [pubmed]
PHST- 2004/07/23 05:00 [medline]
PHST- 2004/05/18 05:00 [entrez]
AID - S0304383503008103 [pii]
AID - 10.1016/j.canlet.2003.11.018 [doi]
PST - ppublish
SO  - Cancer Lett. 2004 Jun 8;209(1):55-65. doi: 10.1016/j.canlet.2003.11.018.