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Uterine epithelial cell estrogen receptor alpha-dependent and -independent genomic profiles that underlie estrogen responses in mice.

ABSTRACT: Estrogens exert their activity through estrogen receptor alpha (ERalpha) to stimulate hypertrophy and hyperplasia in the uterus. A uterine epithelial ERalpha conditional knockout mouse model (Wnt7a(Cre+);Esr1(f/f) or cKO) demonstrated that ERalpha in the epithelial cells was dispensable for an initial uterine proliferative response to 17beta-estradiol (E2) but required for subsequent uterine biological responses. This study aimed to characterize the differential gene expression patterns induced by E2 in the presence or absence of epithelial ERalpha. RNA microarray analysis revealed that approximately 20% of the genes differentially expressed at 2 h were epithelial ERalpha independent, as they were preserved in the cKO uteri. This indicates that early uterine transcripts mediated by stromal ERalpha are sufficient to promote initial proliferative responses. However, more than 90% of the differentially expressed transcripts at 24 h were not regulated in the cKO, indicating that the majority of later transcriptional regulation required epithelial ERalpha, especially those involved in mitosis. This shows that loss of regulation of these later transcripts results in blunted subsequent uterine growth after 3 days of E2 treatment. Additionally, progesterone's ability to inhibit E2-induced epithelial cell proliferation was impaired, consistent with a uterine receptivity defect that contributes to cKO infertility. These transcriptional profiles correlate with our previously observed biological responses, in which the initial proliferative response is independent of epithelial ERalpha and thus dependent on stromal ERalpha, yet epithelial ERalpha is essential for subsequent tissue responsiveness.

SUBMITTER: Winuthayanon W

PROVIDER: S-EPMC4434925 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Uterine epithelial cell estrogen receptor alpha-dependent and -independent genomic profiles that underlie estrogen responses in mice.

Winuthayanon Wipawee W Hewitt Sylvia C SC Korach Kenneth S KS

Biology of reproduction 20140910 5

Estrogens exert their activity through estrogen receptor alpha (ERalpha) to stimulate hypertrophy and hyperplasia in the uterus. A uterine epithelial ERalpha conditional knockout mouse model (Wnt7a(Cre+);Esr1(f/f) or cKO) demonstrated that ERalpha in the epithelial cells was dispensable for an initial uterine proliferative response to 17beta-estradiol (E2) but required for subsequent uterine biological responses. This study aimed to characterize the differential gene expression patterns induced ...[more]

PMID: 25210133

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Project description:Breast cancer resistance to the antiestrogens tamoxifen (OHT) and fulvestrant is accompanied by alterations in both estrogen-dependent and estrogen-independent signaling pathways. Consequently, effective inhibition of both pathways may be necessary to block proliferation of antiestrogen-resistant breast cancer cells. In this study, we examined the effects of apigenin, a dietary plant flavonoid with potential anticancer properties, on estrogen-responsive, antiestrogen-sensitive MCF7 breast cancer cells and two MCF7 sublines with acquired resistance to either OHT or fulvestrant. We found that apigenin can function as both an estrogen and an antiestrogen in a dose-dependent manner. At low concentrations (1 mumol/L), apigenin stimulated MCF7 cell growth but had no effect on the antiestrogen-resistant MCF7 sublines. In contrast, at high concentrations (>10 mumol/L), the drug inhibited growth of MCF7 cells and the antiestrogen-resistant sublines, and the combination of apigenin with either OHT or fulvestrant showed synergistic, growth-inhibitory effects on both antiestrogen-sensitive and antiestrogen-resistant breast cancer cells. To further elucidate the molecular mechanism of apigenin as either an estrogen or an antiestrogen, effects of the drug on estrogen receptor-alpha (ERalpha); transactivation activity, mobility, stability, and ERalpha-coactivator interactions were investigated. Low-dose apigenin enhanced receptor transcriptional activity by promoting interaction between ERalpha and its coactivator amplified in breast cancer-1. However, higher doses (>10 mumol/L) of apigenin inhibited ERalpha mobility (as determined by fluorescence recovery after photobleaching assays), down-regulated ERalpha and amplified in breast cancer-1 expression levels, and inhibited multiple protein kinases, including p38, protein kinase A, mitogen-activated protein kinase, and AKT. Collectively, these results show that apigenin can function as both an antiestrogen and a protein kinase inhibitor with activity against breast cancer cells with acquired resistance to OHT or fulvestrant. We conclude that apigenin, through its ability to target both ERalpha-dependent and ERalpha-independent pathways, holds promise as a new therapeutic agent against antiestrogen-resistant breast cancer.

Dataset Information

Uterine epithelial cell estrogen receptor alpha-dependent and -independent genomic profiles that underlie estrogen responses in mice.

Publications

Uterine epithelial cell estrogen receptor alpha-dependent and -independent genomic profiles that underlie estrogen responses in mice.

Similar Datasets

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