PMID- 22965848
OWN - NLM
STAT- MEDLINE
DCOM- 20130708
LR  - 20211021
IS  - 1868-8500 (Electronic)
IS  - 1868-8497 (Print)
IS  - 1868-8497 (Linking)
VI  - 4
IP  - 1
DP  - 2013 Feb
TI  - Raloxifene inhibits growth of RT4 urothelial carcinoma cells via estrogen 
      receptor-dependent induction of apoptosis and inhibition of proliferation.
PG  - 24-35
LID - 10.1007/s12672-012-0123-9 [doi]
AB  - Bladder cancer is the fifth most common type of cancer in the USA, with over 
      70,000 new cases diagnosed each year. Treatment often involves invasive surgical 
      therapies, as chemotherapy alone is often ineffective and associated with high 
      recurrence rates. Identification of estrogen receptor-beta (ERbeta) in up to 75 % of 
      urinary tumors raises the question of whether this receptor could be targeted to 
      effectively treat bladder cancer. In this study, a panel of five bladder cancer 
      cell lines representing a variety of disease stage and grades were treated with 
      the antiestrogens 4-hydroxytamoxifen, raloxifene, or the pure antagonist ICI 
      182,780. All cell lines were ERbeta positive while only a few expressed estrogen 
      receptor-alpha (ERalpha). Notably, all but the TCCSUP cell line were growth inhibited 
      20-100 % by at least two antiestrogens. Using RT4 cells, we demonstrate that 
      growth inhibition by raloxifene is ER dependent and either ERalpha or ERbeta can mediate 
      this response. Activation of caspase-3 and its effector poly-ADP ribose 
      polymerase (PARP) demonstrate that raloxifene-induced growth inhibition is in 
      part the result of increased apoptosis; this PARP cleavage was ER dependent. 
      Moreover, changes in the expression of cell cycle genes indicate that cell 
      proliferation is also affected. Specifically, raloxifene treatment results in the 
      stabilization of p27 protein, likely via the downregulation of S-phase 
      kinase-associated protein (SKP2). Expression of the negative cell cycle regulator 
      B-cell translocation gene (BTG2) is also increased, while cyclin D1 transcription 
      is reduced. These results indicate that antiestrogens may be useful therapeutics 
      in the treatment of bladder cancer by targeting ER and inhibiting growth via 
      multiple mechanisms.
FAU - Hoffman, Kristi L
AU  - Hoffman KL
AD  - Program in Translational Biology and Molecular Medicine, Baylor College of 
      Medicine, Houston, TX, USA.
FAU - Lerner, Seth P
AU  - Lerner SP
FAU - Smith, Carolyn L
AU  - Smith CL
LA  - eng
GR  - R03 CA119271/CA/NCI NIH HHS/United States
GR  - CA119271/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20120911
PL  - United States
TA  - Horm Cancer
JT  - Hormones & cancer
JID - 101518427
RN  - 0 (ESR1 protein, human)
RN  - 0 (Estrogen Antagonists)
RN  - 0 (Estrogen Receptor alpha)
RN  - 0 (Estrogen Receptor beta)
RN  - 0 (Immediate-Early Proteins)
RN  - 0 (S-Phase Kinase-Associated Proteins)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 094ZI81Y45 (Tamoxifen)
RN  - 136601-57-5 (Cyclin D1)
RN  - 141490-22-4 (BTG2 protein, human)
RN  - 17197F0KYM (afimoxifene)
RN  - 22X328QOC4 (Fulvestrant)
RN  - 4F86W47BR6 (Raloxifene Hydrochloride)
RN  - 4TI98Z838E (Estradiol)
RN  - EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
RN  - EC 3.4.22.- (Caspase 3)
SB  - IM
MH  - Apoptosis/*drug effects/genetics
MH  - Carcinoma, Transitional Cell/*drug therapy/genetics/metabolism/pathology
MH  - Caspase 3/genetics/metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation/*drug effects
MH  - Cyclin D1/genetics/metabolism
MH  - Down-Regulation/drug effects/genetics
MH  - Estradiol/analogs & derivatives/pharmacology
MH  - Estrogen Antagonists/pharmacology
MH  - Estrogen Receptor alpha/genetics/*metabolism
MH  - Estrogen Receptor beta/genetics/*metabolism
MH  - Fulvestrant
MH  - Humans
MH  - Immediate-Early Proteins/genetics/metabolism
MH  - MCF-7 Cells
MH  - Poly(ADP-ribose) Polymerases/genetics/metabolism
MH  - Raloxifene Hydrochloride/*pharmacology
MH  - S-Phase Kinase-Associated Proteins/genetics/metabolism
MH  - Tamoxifen/analogs & derivatives/pharmacology
MH  - Tumor Suppressor Proteins/genetics/metabolism
MH  - Urinary Bladder Neoplasms/*drug therapy/genetics/metabolism/pathology
PMC - PMC3541450
MID - NIHMS407030
COIS- The authors declare that they have no conflict of interest.
EDAT- 2012/09/12 06:00
MHDA- 2013/07/09 06:00
PMCR- 2012/09/11
CRDT- 2012/09/12 06:00
PHST- 2012/07/05 00:00 [received]
PHST- 2012/08/28 00:00 [accepted]
PHST- 2012/09/12 06:00 [entrez]
PHST- 2012/09/12 06:00 [pubmed]
PHST- 2013/07/09 06:00 [medline]
PHST- 2012/09/11 00:00 [pmc-release]
AID - 123 [pii]
AID - 10.1007/s12672-012-0123-9 [doi]
PST - ppublish
SO  - Horm Cancer. 2013 Feb;4(1):24-35. doi: 10.1007/s12672-012-0123-9. Epub 2012 Sep 
      11.