PMID- 10569618
OWN - NLM
STAT- MEDLINE
DCOM- 20000106
LR  - 20190621
IS  - 0022-5347 (Print)
IS  - 0022-5347 (Linking)
VI  - 162
IP  - 6
DP  - 1999 Dec
TI  - Two mutations identified in the androgen receptor of the new human prostate
      cancer cell line MDA PCa 2a.
PG  - 2192-9
AB  - PURPOSE: We have characterized the androgen receptor (AR) in a new human prostate
      cancer cell line, MDA PCa 2a, that has recently been established from a bone
      metastasis of a patient whose cancer exhibited androgen-independent growth.
      MATERIALS AND METHODS: Androgen responsiveness of these cells was assessed by
      measuring the effect of DHT and R1881 on cell growth and PSA secretion. Scatchard
      analysis was used to characterize the affinity and abundance of AR protein. Using
      a PCR based strategy, genomic DNA of the entire coding region of AR gene was
      sequenced to identify possible mutations. RESULTS: These cells express abundant
      AR (Nmax = 685 +/- 149 fmol./mg. protein), but the AR binding affinity (Kd) for
      DHT is only 25 nM, approximately 50-fold lower affinity than the mutated AR in
      LNCaP prostate cancer cells (Kd = 0.5 nM) or the wildtype AR in MCF-7 breast
      cancer cells (Kd = 0.4 nM). Two mutations, L701H and T877A, were identified in
      the ligand binding domain of the AR gene. Compared with LNCaP cells, the new cell
      line is significantly less responsive to DHT and R1881 as well as to other
      androgens such as testosterone, androstenedione, and DHEA. Similar to LNCaP
      cells, the ligand specificity of the AR in MDA PCa 2a cells appears to be relaxed
      and non-androgens such as progesterone and estradiol act as agonists although
      with less potency than in LNCaP cells. Interestingly, in the absence of
      androgens, the new cell line expresses 15-fold higher baseline levels of PSA than
      LNCaP. CONCLUSIONS: Two mutations were identified in the AR gene of the MDA PCa
      2a cell line that are likely responsible for the decreased androgen sensitivity
      and altered ligand specificity observed in these cells. Thus, this new cell line 
      with partial androgen responsiveness and PSA expression can serve as a
      functionally relevant model system of bone metastatic prostate cancer, and can be
      used to investigate the role of AR mutations in prostate cancer and its
      progression to androgen independence.
FAU - Zhao, X Y
AU  - Zhao XY
AD  - Department of Medicine, Stanford University School of Medicine, California, USA.
FAU - Boyle, B
AU  - Boyle B
FAU - Krishnan, A V
AU  - Krishnan AV
FAU - Navone, N M
AU  - Navone NM
FAU - Peehl, D M
AU  - Peehl DM
FAU - Feldman, D
AU  - Feldman D
LA  - eng
GR  - DK42482/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Urol
JT  - The Journal of urology
JID - 0376374
RN  - 0 (Receptors, Androgen)
RN  - EC 3.4.21.77 (Prostate-Specific Antigen)
SB  - IM
MH  - Cell Division
MH  - Humans
MH  - Male
MH  - *Mutation
MH  - Prostate-Specific Antigen/drug effects/metabolism
MH  - Prostatic Neoplasms/*genetics/pathology
MH  - Receptors, Androgen/drug effects/*genetics
MH  - Tumor Cells, Cultured
EDAT- 1999/11/24 00:00
MHDA- 1999/11/24 00:01
CRDT- 1999/11/24 00:00
PHST- 1999/11/24 00:00 [pubmed]
PHST- 1999/11/24 00:01 [medline]
PHST- 1999/11/24 00:00 [entrez]
AID - S0022-5347(05)68158-X [pii]
AID - 10.1016/s0022-5347(05)68158-x [doi]
PST - ppublish
SO  - J Urol. 1999 Dec;162(6):2192-9. doi: 10.1016/s0022-5347(05)68158-x.