17-β-Estradiol Inhibits Transforming Growth Factor-β Signaling and Function in Breast Cancer Cells via Activation of Extracellular Signal-Regulated Kinase through the G Protein-Coupled Receptor 30

Kleuser, Burkhard; Malek, Daniela; Gust, Ronald; Pertz, Heinz H.; Potteck, Henrik

doi:10.1124/mol.108.046854

Cited by 80 publications

(65 citation statements)

References 38 publications

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“…Arterial rings were stretched under 2 g (aorta), 1 g (carotid artery), or 0.5 g (mesenteric and renal artery) of basal tension and allowed to equilibrate for 45 min in Krebs solution bubbled with 95% O2-5% CO2 at 37°C. These basal tensions produced maximal KCl contraction, and further increases in basal tension did not cause further contraction to KCl (72 (21,37), and the percent vascular relaxation was measured. For concentration-response curves, each ER agonist concentration was added, the vascular response was observed until it reached steady state or for 10 min, and the next concentration was then added.…”

Section: Methodsmentioning

confidence: 99%

Adaptive increases in expression and vasodilator activity of estrogen receptor subtypes in a blood vessel-specific pattern during pregnancy

Mata

Reslan

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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RA. Adaptive increases in expression and vasodilator activity of estrogen receptor subtypes in a blood vessel-specific pattern during pregnancy. Am J Physiol Heart Circ Physiol 309: H1679 -H1696, 2015. First published September 25, 2015 doi:10.1152/ajpheart.00532.2015.-Normal pregnancy is associated with adaptive hemodynamic, hormonal, and vascular changes, and estrogen (E 2) may promote vasodilation during pregnancy; however, the specific E 2 receptor (ER) subtype, post-ER signaling mechanism, and vascular bed involved are unclear. We tested whether pregnancy-associated vascular adaptations involve changes in the expression/ distribution/activity of distinct ER subtypes in a blood vessel-specific manner. Blood pressure (BP) and plasma E 2 were measured in virgin and pregnant (day 19) rats, and the thoracic aorta, carotid artery, mesenteric artery, and renal artery were isolated for measurements of ER␣, ER␤, and G protein-coupled receptor 30 [G protein-coupled ER (GPER)] expression and tissue distribution in parallel with relaxation responses to E 2 (all ERs) and the specific ER agonist 4,4=,4Љ-(4-propyl-[1H]-pyrazole-1,3,5-triyl)-tris-phenol (PPT; ER␣), diarylpropionitrile (DPN; ER␤), and G1 (GPER). BP was slightly lower and plasma E 2 was higher in pregnant versus virgin rats. Western blots revealed increased ER␣ and ER␤ in the aorta and mesenteric artery and GPER in the aorta of pregnant versus virgin rats. Immunohistochemistry revealed that the increases in ERs were mainly in the intima and media. In phenylephrineprecontracted vessels, E 2 and PPT caused relaxation that was greater in the aorta and mesenteric artery but similar in the carotid and renal artery of pregnant versus virgin rats. DPN-and G1-induced relaxation was greater in the mesenteric and renal artery than in the aorta and carotid artery, and aortic relaxation to G1 was greater in pregnant versus virgin rats. The nitric oxide synthase inhibitor N -nitro-L-arginine methyl ester with or without the cyclooxygenase inhibitor indomethacin with or without the EDHF blocker tetraethylammonium or endothelium removal reduced E 2, PPT, and G1-induced relaxation in the aorta of pregnant rats, suggesting an endothelium-dependent mechanism, but did not affect E 2-, PPT-, DPN-, or G1-induced relaxation in other vessels, suggesting endothelium-independent mechanisms. E 2, PPT, DPN, and G1 caused relaxation of Ca 2ϩ entry-dependent KCl contraction, and the effect of PPT was greater in the mesenteric artery of pregnant versus virgin rats. Thus, during pregnancy, an increase in ER␣ expression in endothelial and vascular smooth muscle layers of the aorta and mesenteric artery is associated with increased ER␣-mediated relaxation via endothelium-derived vasodilators and inhibition of Ca 2ϩ entry into vascular smooth muscle, supporting a role of aortic and mesenteric arterial ER␣ in pregnancyassociated vasodilation. GPER may contribute to aortic relaxation while enhanced ER␤ expression could mediate other genomic vascular effects during pregnancy.

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Section: Methodsmentioning

confidence: 99%

Adaptive increases in expression and vasodilator activity of estrogen receptor subtypes in a blood vessel-specific pattern during pregnancy

Mata

Reslan

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…ERa blocks TGFb signaling in a nongenomic manner by promoting SMAD2/3 degradation (16) and activation of MAPK through GPR30 (17). Furthermore, it has been demonstrated that SMAD3 and SMAD4 act as coactivators and corepressors, respectively, for ERainduced gene expression (18,19).…”

Section: Introductionmentioning

confidence: 99%

Loss of TGFβ Receptor Type 2 Expression Impairs Estrogen Response and Confers Tamoxifen Resistance

et al. 2015

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One third of the patients with estrogen receptor a (ERa)-positive breast cancer who are treated with the antiestrogen tamoxifen will either not respond to initial therapy or will develop drug resistance. Endocrine response involves crosstalk between ERa and TGFb signaling, such that tamoxifen nonresponsiveness or resistance in breast cancer might involve aberrant TGFb signaling. In this study, we analyzed TGFb receptor type 2 (TGFBR2) expression and correlated it with ERa status and phosphorylation in a cohort of 564 patients who had been randomized to tamoxifen or no-adjuvant treatment for invasive breast carcinoma. We also evaluated an additional four independent genetic datasets in invasive breast cancer. In all the cohorts we analyzed, we documented an association of low TGFBR2 protein and mRNA expression with tamoxifen resistance. Functional investigations confirmed that cell cycle or apoptosis responses to estrogen or tamoxifen in ERa-positive breast cancer cells were impaired by TGFBR2 silencing, as was ERa phosphorylation, tamoxifen-induced transcriptional activation of TGFb, and upregulation of the multidrug resistance protein ABCG2. Acquisition of low TGFBR2 expression as a contributing factor to endocrine resistance was validated prospectively in a tamoxifen-resistant cell line generated by long-term drug treatment. Collectively, our results established a central contribution of TGFb signaling in endocrine resistance in breast cancer and offered evidence that TGFBR2 can serve as an independent biomarker to predict treatment outcomes in ERa-positive forms of this disease.

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“…The effects of 17-b E 2 on these tissues are either mediated through ER binding to EREs directly regulating gene expression, via ER interaction with other transcription factors or by nonnuclear actions that seem to be mediated by membrane-bound ERs (Rae & Johnson 2005, Kleuser et al 2008, Peng & Jordan 2008. Estrogens are known to stimulate proliferation of hormone-dependent tissues for example by activation of cell cycle genes (Kashima et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Knockdown of ICB-1 gene enhanced estrogen responsiveness of ovarian and breast cancer cells

Konwisorz¹,

Springwald²,

Haselberger³

et al. 2010

Endocrine-Related Cancer

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ICB-1 chromosome 1 open reading frame 38 (C1orf38) is a human gene initially described by our group to be involved in differentiation processes of cancer cells. Recently, we have reported ICB-1 as a novel estrogen target gene and identified an estrogen response element in its promoter. In this study, we examined the role of ICB-1 in regulation of proliferation of breast and ovarian cancer cells. We knocked down its expression in estrogen-dependent MCF-7 breast cancer cells and hormone-unresponsive SK-OV-3 ovarian cancer cells by stable transfection with a specific shRNA plasmid followed by G-418 selection. Knockdown of ICB-1 enabled a considerable estrogen response of SK-OV-3 cells in terms of proliferation. This transformation of SK-OV-3 cells into an estrogen-responsive phenotype was accompanied by upregulation of estrogen receptor a (ERa) expression and a significant decrease of ERb expression on the mRNA level. Expression of ERa-dependent genes progesterone receptor, pS2, fibulin 1c, and c-fos was elevated in SK-OV-3 cells stably expressing ICB-1 shRNA. In MCF-7 cells, ICB-1 knockdown exerted similar effects on gene expression, supporting a general role of ICB-1 in estrogen responsiveness. Our data suggest that differentiation-associated gene ICB-1 might exert antagonistic actions on cellular estrogen response, which can result in inhibition of estradiol-triggered proliferation. The molecular mechanisms mediating this inhibitory effect of ICB-1 on estrogen signaling are suggested to be limitation of ERa transcript levels but sustaining high levels of ERb, reducing both activation of ERa target genes and cellular proliferation. The identification of ICB-1 as a new player in endocrine-related cancer encourages further studies on the significance of this gene in cancer development and therapy.

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17-β-Estradiol Inhibits Transforming Growth Factor-β Signaling and Function in Breast Cancer Cells via Activation of Extracellular Signal-Regulated Kinase through the G Protein-Coupled Receptor 30

Cited by 80 publications

References 38 publications

Adaptive increases in expression and vasodilator activity of estrogen receptor subtypes in a blood vessel-specific pattern during pregnancy

Adaptive increases in expression and vasodilator activity of estrogen receptor subtypes in a blood vessel-specific pattern during pregnancy

Loss of TGFβ Receptor Type 2 Expression Impairs Estrogen Response and Confers Tamoxifen Resistance

Knockdown of ICB-1 gene enhanced estrogen responsiveness of ovarian and breast cancer cells

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