TY - JOUR
T1 - Characterization of the weak estrogen receptor α agonistic activity of exemestane
AU - Masri, Selma
AU - Lui, Ki
AU - Phung, Sheryl
AU - Ye, Jingjing
AU - Zhou, Dujin
AU - Wang, Xin
AU - Chen, Shiuan
N1 - Funding Information:
Acknowledgement S. Masri was supported by NIH pre-doctoral training fellowship CA123691 and S. Chen by NIH grants CA044735 and ES08258.
PY - 2009/8
Y1 - 2009/8
N2 - Third generation aromatase inhibitors (AI) have shown good clinical efficacy in comparison to the anti-estrogen tamoxifen. The steroidal AI, exemestane (EXE) has previously been shown to act as an androgen, but this report demonstrates the estrogen-like activity of EXE. Based on genome-wide microarray analysis, high correlation was seen between EXE-Only (EXE O, hormone- free) and hormone-containing AI-resistant lines. In addition, the top regulated genes in the EXE O lines were mostly estrogen-responsive genes. This estrogen-like activity of EXE was further validated using estrogen receptor (ER) activity assays, where in comparison to 17β-estradiol (E2), EXE was able to induce ER activity, though at a higher concentration. Also, this EXE-mediated ER activity was blocked by the ER antagonist ICI as well as the ERα-specific antagonist methyl-piperidino-pyrazole (MPP). Similarly, EXE was able to induce proliferation of breast cancer cell lines, MCF-7 and MCF-7aro, as well as activate transcription of known estrogen-responsive genes, i.e., PGR, pS2 and AREG. These results suggest that EXE does have weak estrogen-like activity.
AB - Third generation aromatase inhibitors (AI) have shown good clinical efficacy in comparison to the anti-estrogen tamoxifen. The steroidal AI, exemestane (EXE) has previously been shown to act as an androgen, but this report demonstrates the estrogen-like activity of EXE. Based on genome-wide microarray analysis, high correlation was seen between EXE-Only (EXE O, hormone- free) and hormone-containing AI-resistant lines. In addition, the top regulated genes in the EXE O lines were mostly estrogen-responsive genes. This estrogen-like activity of EXE was further validated using estrogen receptor (ER) activity assays, where in comparison to 17β-estradiol (E2), EXE was able to induce ER activity, though at a higher concentration. Also, this EXE-mediated ER activity was blocked by the ER antagonist ICI as well as the ERα-specific antagonist methyl-piperidino-pyrazole (MPP). Similarly, EXE was able to induce proliferation of breast cancer cell lines, MCF-7 and MCF-7aro, as well as activate transcription of known estrogen-responsive genes, i.e., PGR, pS2 and AREG. These results suggest that EXE does have weak estrogen-like activity.
KW - Aromatase inhibitors
KW - Estrogen receptor
KW - Exemestane
UR - http://www.scopus.com/inward/record.url?scp=70349578803&partnerID=8YFLogxK
U2 - 10.1007/s10549-008-0151-x
DO - 10.1007/s10549-008-0151-x
M3 - Article
C2 - 18677558
AN - SCOPUS:70349578803
SN - 0167-6806
VL - 116
SP - 461
EP - 470
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
IS - 3
ER -
