TY - JOUR
T1 - Changes in expression of steroid receptors, their downstream target genes and their associated co-regulators during the sequential acquisition of tamoxifen resistance in vitro
AU - Scott, D. J.
AU - Parkes, A. T.
AU - Ponchel, F.
AU - Cummings, M.
AU - Poola, I.
AU - Speirs, V.
PY - 2007/9
Y1 - 2007/9
N2 - Tamoxifen resistance (TAMr) in breast cancer is a serious clinical dilemma, with no satisfactory explanation. We hypothesised that changes in the expression of steroid hormone receptors (ERα, ERβ), their downstream target genes (PR, pS2) and their associated co-regulators (AIB-1, SRC-1, SRA, NCoR-1, SMRT and REA) could be related to the acquisition of TAMr. To test this hypothesis, we developed in vitro TAMr cell line models by continuous exposure of MCF-7 cells to 4-hydroxytamoxifen (4-HT) over 12 (MCF-7MMU1) and 21 (MCF-7MMU2) months, respectively and examined the expression of the above by Western blotting and immunohistochemistry. In addition, we further examined the changes in global gene expression in TAMr cells in comparison with TAM-sensitive cells by microarray analysis. We report here that acquisition of TAMr is associated with changes in the expression of PR, pS2 and several co-activators, but not ERs. In addition, genes associated with cell cycle, cell adhesion and extracellular matrix, were up-regulated while those associated with apoptosis or growth factors/hormones were down-regulated. Based on our results, it appears that increased co-activator expression, in concert with alterations in genes associated with controlling cell proliferation and survival contribute to TAMr in breast cancer.
AB - Tamoxifen resistance (TAMr) in breast cancer is a serious clinical dilemma, with no satisfactory explanation. We hypothesised that changes in the expression of steroid hormone receptors (ERα, ERβ), their downstream target genes (PR, pS2) and their associated co-regulators (AIB-1, SRC-1, SRA, NCoR-1, SMRT and REA) could be related to the acquisition of TAMr. To test this hypothesis, we developed in vitro TAMr cell line models by continuous exposure of MCF-7 cells to 4-hydroxytamoxifen (4-HT) over 12 (MCF-7MMU1) and 21 (MCF-7MMU2) months, respectively and examined the expression of the above by Western blotting and immunohistochemistry. In addition, we further examined the changes in global gene expression in TAMr cells in comparison with TAM-sensitive cells by microarray analysis. We report here that acquisition of TAMr is associated with changes in the expression of PR, pS2 and several co-activators, but not ERs. In addition, genes associated with cell cycle, cell adhesion and extracellular matrix, were up-regulated while those associated with apoptosis or growth factors/hormones were down-regulated. Based on our results, it appears that increased co-activator expression, in concert with alterations in genes associated with controlling cell proliferation and survival contribute to TAMr in breast cancer.
KW - Breast cancer
KW - Microarray
KW - Tamoxifen resistance
UR - http://www.scopus.com/inward/record.url?scp=38449110253&partnerID=8YFLogxK
U2 - 10.3892/ijo.31.3.557
DO - 10.3892/ijo.31.3.557
M3 - Article
C2 - 17671682
AN - SCOPUS:38449110253
SN - 1019-6439
VL - 31
SP - 557
EP - 565
JO - International Journal of Oncology
JF - International Journal of Oncology
IS - 3
ER -