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ABSTRACT: Objective. Estrogen receptor β (ERβ) is expressed in the majority of triple-
negative breast cancer cases. In this study, we tested to what extent
treatment of triple-negative breast cancer cell lines with two highly specific
ERβ agonists would affect their invasiveness and motility.
Methods. Cellular invasion was assessed by means of a modified Boyden
chamber with a membrane pore size of 8 μm coated with a soluble basement
membrane extract. Migration was measured using the same model
system without ECM. Relative cell numbers were assessed by means
of the fluorimetric Cell Titer Blue Assay (Promega). Gene expression
was examined by RT-qPCR using a Light Cycler 2.0 device (Roche) and
by Western Blot analysis.
Results. Selective ERβ agonist ERB-041 significantly reduced invasiveness
of the triple negative breast cancer cell lines MDA-MB-231 and
HS578T in vitro in a dose-dependent manner. ERB-041 inhibited invasion
of MDA-MB-231 cells down to 70.7% (p<0.01) and of HS578T cells
down to 65% (p<0.01). The second highly specific ERβ agonist tested,
Liquiritigenin, inhibited invasion of MDA-MB-231 cancer cells down
to 70.2% (100 nM; p<0.05), whereas HS578T cells were not affected. In
contrast to ERB-041, Liquiritigenin also inhibited migration of MDAMB-
231 cells in a Boyden chamber assay. The inhibitory effects of ERB-
041 and liquiritigenin on invasiveness of triple-negative breast cancer
cells were accompanied by a strong decrease of Stromelysin 3 (MMP-11)
gene expression by about 50% and by upregulation of ERb2 mRNA levels
by 77.5% (p<0.01). Expression of other MMPs tested (MMP-1, MMP-2,
MMP-9, MMP-13, MMP-14, MMP-18), of Cathepsin L, ERβ1 and ERβ5
was not or only slightly affected by treatment with the ERβ agonists.
Conclusions. We demonstrated that highly specific ERβ agonists were
able to significantly reduce invasiveness of triple negative breast cancer
cells in vitro. Our data suggest that this effect was mediated by downregulation
of Stromelysin 3 (MMP-11) expression. Whether ERβ agonists
might be useful drugs in the treatment of triple-negative breast cancer
has to be evaluated in further animal and clinical studies.
Journal of Cancer Research and Clinical Oncology 02/2012; · 2.56 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Objective. Estrogen receptor β (ERβ) is expressed in the majority of triple-
negative breast cancer cases. In this study, we tested to what extent
treatment of triple-negative breast cancer cell lines with two highly specific
ERβ agonists would affect their invasiveness and motility.
Methods. Cellular invasion was assessed by means of a modified Boyden
chamber with a membrane pore size of 8 μm coated with a soluble basement
membrane extract. Migration was measured using the same model
system without ECM. Relative cell numbers were assessed by means
of the fluorimetric Cell Titer Blue Assay (Promega). Gene expression
was examined by RT-qPCR using a Light Cycler 2.0 device (Roche) and
by Western Blot analysis.
Results. Selective ERβ agonist ERB-041 significantly reduced invasiveness
of the triple negative breast cancer cell lines MDA-MB-231 and
HS578T in vitro in a dose-dependent manner. ERB-041 inhibited invasion
of MDA-MB-231 cells down to 70.7% (p<0.01) and of HS578T cells
down to 65% (p<0.01). The second highly specific ERβ agonist tested,
Liquiritigenin, inhibited invasion of MDA-MB-231 cancer cells down
to 70.2% (100 nM; p<0.05), whereas HS578T cells were not affected. In
contrast to ERB-041, Liquiritigenin also inhibited migration of MDAMB-
231 cells in a Boyden chamber assay. The inhibitory effects of ERB-
041 and liquiritigenin on invasiveness of triple-negative breast cancer
cells were accompanied by a strong decrease of Stromelysin 3 (MMP-11)
gene expression by about 50% and by upregulation of ERb2 mRNA levels
by 77.5% (p<0.01). Expression of other MMPs tested (MMP-1, MMP-2,
MMP-9, MMP-13, MMP-14, MMP-18), of Cathepsin L, ERβ1 and ERβ5
was not or only slightly affected by treatment with the ERβ agonists.
Conclusions. We demonstrated that highly specific ERβ agonists were
able to significantly reduce invasiveness of triple negative breast cancer
cells in vitro. Our data suggest that this effect was mediated by downregulation
of Stromelysin 3 (MMP-11) expression. Whether ERβ agonists
might be useful drugs in the treatment of triple-negative breast cancer
has to be evaluated in further animal and clinical studies.
Deutscher Krebskongress 2012, Berlin; 02/2012
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S Schimanski,
P J Wild, O Treeck,
F Horn,
A Sigruener,
C Rudolph,
H Blaszyk,
M Klinkhammer-Schalke,
O Ortmann,
A Hartmann,
G Schmitz
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ABSTRACT: ATP-binding cassette transporters ABCA3 and ABCA1 are related to a differentiated, lipid-secreting phenotype of type II pneumocytes. Since mammary gland epithelial cells also show pronounced lipid metabolism and secretion, we investigated the expression of these proteins in normal as well as in neoplastic breast tissue. Normal human breast tissue, breast cancer cell lines, and 162 tumor samples of patients with primary unilateral invasive breast cancer were analyzed for ABCA3 and ABCA1 protein expression by immunohistochemistry using tissue microarrays. Strong ABCA3 and ABCA1 expression was found in the inner layer of normal mammary gland epithelium. Concurrent cytoplasmic ABCA3 and ABCA1 immunoreactivity was found in 9 of 11 breast cancer cell lines. ABCA3 and ABCA1 were shown to be differentially expressed in human breast cancer. Loss of ABCA3 staining was significantly associated with positive nodal status and negative progesterone receptor expression. In multivariate analysis, diminished ABCA3 expression proved to be a significant, independent and adverse risk factor for tumor recurrence. ABCA1 expression was associated with positive lymph nodes, but not significantly associated with tumor recurrence or breast cancer-specific survival. ABCA3 and ABCA1 are strongly expressed in normal mammary gland epithelium. Decreased ABCA3 expression in breast cancer seems to be associated with poor prognosis.
Hormone and Metabolic Research 11/2009; 42(2):102-9. · 2.19 Impact Factor
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ABSTRACT: Serum levels of adiponectin are inversely associated with breast cancer risk. In this study, its effect on growth and gene expression of MCF-7 breast cancer cells and MCF-10A human mammary epithelial cells was compared. The antiproliferative effect of adiponectin on MCF-10A cells was more pronounced and was accompanied by elevated transcript levels of caspase 1, ERbeta2, ERbeta5, TR2 and USP2. Our data suggest that upregulation of genes with known growth inhibitory or apoptotic functions in mammary epithelial cells might contribute to the protective action of this adipocytokine.
British Journal of Cancer 10/2008; 99(8):1246-50. · 5.04 Impact Factor
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ABSTRACT: Cellular response to oestradiol stimuli is mediated both by oestrogen receptor (ER) binding to oestrogen response elements (EREs) and by non-nuclear actions like activation of mitogen-activated protein kinase (MAPK) signal transduction. Therefore, oestradiol stimuli might be able to interfere with the action of antitumoral substances directed against receptor tyrosine kinase signalling. We investigated the effect of oestradiol on the inhibition of HER2 signalling by trastuzumab (Herceptin) in two human endometrial adenocarcinoma cell lines. Activation of the extracellular signal-regulated kinase (ERK-1/2), a major mediator of HER2 signalling, was measured by means of western blotting experiments and ERE activation was determined in transient reporter-gene assays. In endometrial Ishikawa and HEC-1A adenocarcinoma cells, HER2 signalling was inhibited by trastuzumab only in the absence of oestradiol. We were able to demonstrate that oestradiol counteracted the inhibitory effects of trastuzumab by rapid phosphorylation of ERK-1/2, a kinase downstream of the HER2 receptor. The pure anti-oestrogen ICI 182,780 was able to restore both the trastuzumab-triggered inhibition of the ERK-1/2 pathway and the antiproliferative action of this substance in Ishikawa cells. Our data suggest that combinations of trastuzumab with anti-oestrogens may be effective in the treatment of endometrial cancers with a positive ER and HER2 receptor status.
European Journal of Cancer 07/2003; 39(9):1302-9. · 5.54 Impact Factor
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ABSTRACT: Cultured HEC1B human endometrial adenocarcinoma cells respond to reconstituted basement membrane (Matrigel) by morphological and functional differentiation in vitro. Our goal is to identify genes involved in this differentiation process. By means of rt-PCR, we were able to isolate the novel 2.4 kb Matrigel-induced transcript icb-1 containing an open reading frame predicting a 31.7 kDa protein. The time-dependent induction of icb-1 gene expression by basement membrane was confirmed by Northern blot experiments. In a data bank search, several EST homologues corresponding to the 3' untranslated region could be found. In summary, icb-1 as a new tool enables us to study molecular mechanisms of cell-matrix interactions contributing to carcinogenesis.
FEBS Letters 05/1998; 425(3):426-30. · 3.54 Impact Factor
