Comparative effects of estradiol, methyl-piperidino-pyrazole, raloxifene, and ICI 182 780 on gene expression in the murine uterus.
Selective estrogen receptor modulators (SERMs) are potentially useful in treating various endometrial disorders, including endometrial cancer, as they block some of the detrimental effects of estrogen. It remains unclear whether each SERM regulates a unique subset of genes and, if so, whether the combination of a SERM and 17beta-estradiol has an additive or synergistic effect on gene expression. We performed microarray analysis with Affymetrix Mouse Genome 430 2.0 short oligomer arrays to determine gene expression changes in uteri of ovariectomized mice treated with estradiol (low and high dose), methyl-piperidino-pyrazole (MPP), ICI 182 780, raloxifene, and combinations of high dose of estradiol with one of the SERM and dimethyl sulfoxide (DMSO) vehicle control. The nine treatments clustered into two groups, with MPP, raloxifene, and high dose of estradiol in one, and low dose of estradiol, ICI + estradiol, ICI, MPP + estradiol, and raloxifene + estradiol in the second group. Surprisingly, combining a high dose of estradiol with a SERM markedly increased (P<0.02) the number of regulated genes compared with each individual treatment. Analysis of expression for selected genes in uteri of estradiol and SERM-treated mice by quantitative (Q)RT-PCR generally supported the microarray results. For some cancer-associated genes, including Klk1, Ihh, Cdc45l, and Cdca8, administration of MPP or raloxifene with estradiol resulted in greater expression than estradiol alone (P<0.05). By contrast, ICI 182 780 suppressed more genes governing DNA replication compared with MPP and raloxifene treatments. Therefore, ICI 182 780 might be superior to MPP and raloxifene to treat estrogen-induced endometrial cancer in women.
Davis
Angela M
AM
Department of Biomedical Sciences, 440F Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, Missouri 65211, USA.
Mao
Jiude
J
Naz
Bushra
B
Kohl
Jessica A
JA
Rosenfeld
Cheryl S
CS
D000818:Animals; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D015870:Gene Expression / Q000187:drug effects; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D010052:Ovariectomy; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism
C524478:1,3-bis(4-hydroxyphenyl)-4-methyl-5-(4-(2-piperidinylethoxy)phenol)-1H-pyrazole; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D004967:Estrogens; D010880:Piperidines; D011720:Pyrazoles; D000077267:Fulvestrant; D020849:Raloxifene Hydrochloride; D004958:Estradiol