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This Article Accepted manuscript (PDF) Supplementary Data All Versions of this Article: JME-08-0029v1 41/4/205    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Davis, A. Articles by Rosenfeld, C. PubMed PubMed Citation Articles by Davis, A. Articles by Rosenfeld, C.

A Davis, Biomedical Sciences, University of Missouri, Columbia, United States
J Mao, Biomedical Sciences, University of Missouri, Columbia, United States
B Naz, Biomedical Sciences, University of Missouri, Columbia, United States
J Kohl, Biomedical Sciences, University of Missouri, Columbia, United States
C Rosenfeld, Biomedical Sciences, University of Missouri - Columbia, Columbia, 65211, United States

Correspondence: Cheryl Rosenfeld, Email: rosenfeldc{at}missouri.edu

Abstract

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 sub-set of genes, and if so, whether combination of a SERM and 17β-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, combinations of high dose of estradiol with one of the SERM and 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 to 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). In contrast, ICI 182,780 suppressed more genes governing DNA replication compared to MPP and raloxifene treatments. Therefore, ICI 182,780 might be superior to MPP and raloxifene to treat estrogen-induced endometrial cancer in women.