Oligonucleotide Squelching Reveals the Mechanism of Estrogen Receptor Autologous Down-Regulation

Santagati, Sabrina; Gianazza, Elisabetta; Agrati, Paola; Vegeto, Elisabetta; Patrone, Cesare; Pollio, Giuseppe; Maggi, Adriana

doi:10.1210/mend.11.7.9936

Cited by 38 publications

(28 citation statements)

References 63 publications

(55 reference statements)

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“…Our results are consistent with other studies in which various concentrations of 17 -estradiol were used (Berthois et al 1990, Alarid et al 1999. Some reports have indicated an association of ER mRNA levels and protein levels after 17 -estradiol and other antiestrogen treatments (Saceda et al 1988, Santagati et al 1997. ER protein degradation was reported to be dependent on estrogeninduced proteasome-mediated proteolysis instead of DNA transcription (Alarid et al 1999).…”

Section: Discussionsupporting

confidence: 92%

Suppression of cell proliferation and regulation of estrogen receptor alpha signaling pathway by arsenic trioxide on human breast cancer MCF-7 cells

Chow

Chan²,

Fung

2004

Journal of Endocrinology

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In recent years, breast cancers have aroused much concern. Together with a growing incidence all over the world, the development of drug resistance to tamoxifen, the most commonly prescribed chemotherapeutic drug for breast cancer patients, has highlighted the importance of developing a new chemotherapeutic drug in combating breast cancer. With the aim of treating breast cancers, the anti-tumor effects of arsenic trioxide in MCF-7 cells have been studied.MCF-7 cells are estrogen responsive cells which mimic breast cancers at the early stage. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and direct cell counting were used to measure cell proliferation. The mechanisms of action were elucidated through the measurement of estrogen receptor (ER) binding, mRNA and protein levels of ER and its activity.We have demonstrated that arsenic trioxide was capable of reducing cell survival in MCF-7 cells via the suppression of the estrogen-induced growth stimulatory effects in MCF-7 cells. Arsenic trioxide was shown to suppress the action of estrogen through the regulation of the ER signaling pathway. Arsenic trioxide could downregulate ER mRNA and protein levels without competing with estrogen for ER binding. Arsenic trioxide also inhibited the transcription activity mediated by the ER signaling pathway and ultimately it down-regulated c-myc protein expression and inhibited cell entry to S phase under estrogen's stimulation.In conclusion, arsenic trioxide could inhibit the growth of MCF-7 cells by reducing the growth stimulatory effect of estrogen. As estrogen is a primary risk factor in promoting the growth of breast tumor cells, the antiestrogenicity exhibited by arsenic trioxide sheds light on the therapy of breast cancer.

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Section: Discussionsupporting

confidence: 92%

Suppression of cell proliferation and regulation of estrogen receptor alpha signaling pathway by arsenic trioxide on human breast cancer MCF-7 cells

Chow

Chan²,

Fung

2004

Journal of Endocrinology

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“…1A). Given that decreased levels of ER␣ by agonists have been reported as an additional hallmark of receptor activation (Santagati et al, 1997), we ascertained the expression and potential regulation of ER␣ by treatments in WRO and FRO cells. Using an anti-ER␣ antibody raised against the C-terminal domain (F-10), we detected a single ER␣ isoform with a smaller size (less than 48 kDa) with respect to ER␣ wild type (66 kDa) (Fig.…”

Section: E2 G and Oht Neither Transactivate Nor Regulate The Expresmentioning

confidence: 99%

17β-Estradiol, Genistein, and 4-Hydroxytamoxifen Induce the Proliferation of Thyroid Cancer Cells through the G Protein-Coupled Receptor GPR30

Vivacqua¹,

Bonofiglio²,

Albanito³

et al. 2006

Mol Pharmacol

266

229

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The higher incidence of thyroid carcinoma (TC) in women during reproductive years compared with men and the increased risk associated with the therapeutic use of estrogens have suggested a pathogenetic role exerted by these steroids in the development of TC. In the present study, we evaluated the potential of 17␤-estradiol (E2), genistein (G), and 4-hydroxytamoxifen (OHT) to regulate the expression of diverse estrogen target genes and the proliferation of human WRO, FRO, and ARO thyroid carcinoma cells, which were used as a model system. We have ascertained that ARO cells are devoid of estrogen receptors (ERs), whereas both WRO and FRO cells express a single variant of ER␣ that was neither transactivated, modulated, nor translocated into the nucleus upon treatment with ligands. However, E2, G, and OHT were able either to induce the transcriptional activity of c-fos promoter constructs, including those lacking the estrogen-responsive elements, or to increase c-fos, cyclin A, and D1 expression. It is noteworthy that we have demonstrated that the G protein-coupled receptor 30 (GPR30) and the mitogen-activated protein kinase (MAPK) pathway mediate both the up-regulation of c-fos and the growth response to E2, G, and OHT in TC cells studied, because these stimulatory effects were prevented by silencing GPR30 and using the MEK inhibitor 2Ј-amino-3Ј-methoxyflavone (PD 98059). Our findings provide new insight into the molecular mechanisms through which estrogens may induce the progression of TC.

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“…Leptin Down-regulates ER␣ Expression-E 2 is known to down-regulate the levels of ER␣ in breast cancer cell line through an increased turnover of the E 2 -activated ER␣ protein and a reduced transcription rate of its own gene (46). This down-regulation represents an additional hallmark of ER␣ activation by an agonist.…”

Section: Leptin Modulates Er␣ Nuclear Immunoreactivity In Mcf-7mentioning

confidence: 99%

Leptin Induces, via ERK1/ERK2 Signal, Functional Activation of Estrogen Receptor α in MCF-7 Cells

Catalano

Mauro

Marsico

et al. 2004

Journal of Biological Chemistry

247

185

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Leptin is a hormone with multiple biological actions, produced predominantly by adipose tissue. In humans, plasma levels correlate with total body fat, and high concentrations occur in obese women. Among its functions, leptin is able to stimulate normal and tumor cell growth. We demonstrated that leptin induces aromatase activity in MCF-7 cells evidencing its important role in enhancing in situ estradiol production and promoting estrogen-dependent breast cancer progression. Estrogen receptor ␣ (ER␣), which plays an essential role in breast cancer development, can be transcriptionally activated in a ligand-independent manner. Taking into account that unliganded ER␣ is an effector of mitogenactivated protein kinase (MAPK) signal and that leptin is able, via Janus kinase, to activate the Ras-dependent MAPK pathway, in the present study we investigate the ability of leptin to transactivate ER␣. We provided evidence that leptin is able to reproduce the classic features of ER␣ transactivation in a breast cancer cell line: nuclear localization, down-regulation of its mRNA and protein levels, and up-regulation of a classic estrogendependent gene such as pS2. Transactivation experiments with a transfected reporter gene for nuclear ER showed an activation of ER␣ either in MCF-7 or in HeLa cells. Using a dominant negative ERK2 or the MAPK inhibitor PD 98059, we showed that leptin activates the ER␣ through the MAPK pathway. The N-terminal transcriptional activation function 1 appears essential for the leptin response. Finally, it is worth noting that leptin exposure potentates also the estradiol-induced activation of ER␣. Thus, we are able to demonstrate that the amplification of estrogen signal induced by leptin occurs through an enhancing in situ E 2 production as well as a direct functional activation of ER␣.

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Oligonucleotide Squelching Reveals the Mechanism of Estrogen Receptor Autologous Down-Regulation

Cited by 38 publications

References 63 publications

Suppression of cell proliferation and regulation of estrogen receptor alpha signaling pathway by arsenic trioxide on human breast cancer MCF-7 cells

Suppression of cell proliferation and regulation of estrogen receptor alpha signaling pathway by arsenic trioxide on human breast cancer MCF-7 cells

17β-Estradiol, Genistein, and 4-Hydroxytamoxifen Induce the Proliferation of Thyroid Cancer Cells through the G Protein-Coupled Receptor GPR30

Leptin Induces, via ERK1/ERK2 Signal, Functional Activation of Estrogen Receptor α in MCF-7 Cells

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