The oestrogen-like effect of 4-hydroxytamoxifen on induction of transforming growth factor alpha mRNA in MDA-MB-231 breast cancer cells stably expressing the oestrogen receptor

Levenson, Anait S.; Tonetti, Debra A.; Jordan, V. Craig

doi:10.1038/bjc.1998.301

Cited by 52 publications

(53 citation statements)

References 43 publications

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“…The proliferation of many carcinoma cells in vitro and in vivo is in part regulated by the synthesis and autocrine actions of ligands such as transforming growth factor a (TGFa) Levenson et al, 1998) and vascular endothelial growth factor (VEGF) (Slevin et al, 2000;Hossain et al, 2000;Mazure et al, 1997;Zundel et al, 2000). Irradiation of tumor cells can both increase expression of TGFa and activate the EGFR, and this has been proposed to increase the proliferative rate of surviving cells (Levenson et al, 1998;Baselga et al, 1996;SchmidtUllrich et al, 1992;Putz et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

“…Irradiation of tumor cells can both increase expression of TGFa and activate the EGFR, and this has been proposed to increase the proliferative rate of surviving cells (Levenson et al, 1998;Baselga et al, 1996;SchmidtUllrich et al, 1992;Putz et al, 1999). Increased proliferative rates and poor prognosis of carcinomas in vivo are also correlated with increased expression of the EGFR (Baselga et al, 1996;Schmidt-Ullrich et al, 1992;Putz et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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Ionizing radiation modulates vascular endothelial growth factor (VEGF) expression through multiple mitogen activated protein kinase dependent pathways

et al. 2001

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ionizing radiation modulates vascular endothelial growth factor (VEGF) expression through multiple mitogen activated protein kinase dependent pathways

et al. 2001

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“…Sp1, Ap-1) to initiate responsiveness of other target genes (Klinge, 2001;Nilsson et al, 2001). Overall, if we consider that (1) the level of ER protein goes down with E2, Ral and ICI treatments in these cells (Levenson et al, 1998c;Liu et al, 2001) and (2) the Atlas Arrays we used were spotted with PCR-amplified cDNAs for 588 cancer-related genes with a very few E2-responsive genes with putative EREs in their promoter regions, it is fair to say that we are only detecting changes in non-ER-mediated genes. Among E2-responsive genes were TGFa, VEGF, BRCA1 on the array.…”

Section: Discussionmentioning

confidence: 96%

Molecular classification of selective oestrogen receptor modulators on the basis of gene expression profiles of breast cancer cells expressing oestrogen receptor α

Levenson¹,

Kliakhandler²,

Svoboda³

et al. 2002

Br J Cancer

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The purpose of this study was to classify selective oestrogen receptor modulators based on gene expression profiles produced in breast cancer cells expressing either wtERa or mutant 351 ERa. In total, 54 microarray experiments were carried out by using a commercially available Atlas cDNA Expression Arrays (Clontech), containing 588 cancer-related genes. Nine sets of data were generated for each cell line following 24 h of treatment: expression data were obtained for cells treated with vehicle EtOH (Control); with 10 79 or 10 78 M oestradiol; with 10 76 M 4-hydroxytamoxifen; with 10 76 M raloxifene; with 10 76 M idoxifene, with 10 76 M EM 652, with 10 76 M GW 7604; with 5610 75 M resveratrol and with 10 76 M ICI 182,780. We developed a new algorithm 'Expression Signatures' to classify compounds on the basis of differential gene expression profiles. We created dendrograms for each cell line, in which branches represent relationships between compounds. Additionally, clustering analysis was performed using different subsets of genes to assess the robustness of the analysis. In general, only small differences between gene expression profiles treated with compounds were observed with correlation coefficients ranged from 0.83 to 0.98. This observation may be explained by the use of the same cell context for treatments with compounds that essentially belong to the same class of drugs with oestrogen receptors related mechanisms. The most surprising observation was that ICI 182,780 clustered together with oestrodiol and raloxifene for cells expressing wtERa and clustered together with EM 652 for cells expressing mutant 351 ERa. These data provide a rationale for a more precise and elaborate study in which custom made oligonucleotide arrays can be used with comprehensive sets of genes known to have consensus and putative oestrogen response elements in their promoter regions.

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“…Northern Blot Analysis-TGF␣ mRNA levels were assessed by Northern blot analyses as described previously (23). pS2 probe was generated by reverse transcription-PCR.…”

Section: Methodsmentioning

confidence: 99%

“…However, the agonist activity of 4-OHT is relatively low. We have developed an assay system using MDA-MB-231 cells stably transfected with ER␣ cDNA and an endogenous TGF␣ gene as the reporter in which SERMs show significantly higher agonist activities (18,23). As shown in Fig.…”

Section: Comparison Of Transient and Stable Transfection In Assessmenmentioning

confidence: 99%

Structure-Function Relationships of the Raloxifene-Estrogen Receptor-α Complex for Regulating Transforming Growth Factor-α Expression in Breast Cancer Cells

Liu¹,

Park²,

Bentrem³

et al. 2002

Journal of Biological Chemistry

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Amino acid Asp-351 in the ligand binding domain of estrogen receptor ␣ (ER␣) plays an important role in regulating the estrogen-like activity of selective estrogen receptor modulator-ER␣ complexes. 4-Hydroxytamoxifen is a full agonist at a transforming growth factor ␣ target gene in situ in MDA-MB-231 human breast cancer cells stably transfected with the wild-type ER␣. In contrast, raloxifene (Ral), which is also a selective estrogen receptor modulator, is a complete antiestrogen in this system. Because D351G ER␣ allosterically silences activation function-1 activity in the 4-hydroxytamoxifen-ER␣ complex with the complete loss of estrogenlike activity, we examined the converse interaction of amino acid 351 and the piperidine ring of the antiestrogen side chain of raloxifene to enhance estrogen-like action. MDA-MB-231 cells were either transiently or stably transfected with Asp-351 (the wild type), D351E, D351Y, or D351F ER␣ expression vectors. Profound differences in the agonist and antagonist actions of Ral⅐ER␣ complexes were noted only in stable transfectants. The agonist activity of the Ral⅐ER␣ complex was enhanced with D351E and D351Y ER␣, but raloxifene lost its agonist activity with D351F ER␣. The distance between the piperidine nitrogen of raloxifene and the negative charge of amino acid 351 was critical for estrogen-like actions. The role of the piperidine ring in neutralizing Asp-351 was addressed using compound R1h, a raloxifene derivative replacing the nitrogen on its piperidine ring with a carbon to form cyclohexane. The derivative was a potent agonist with wild type ER␣. These results support the concept that the side chain of raloxifene shields and neutralizes the Asp-351 to produce an antiestrogenic ER␣ complex. Alteration of either the side chain or its relationship with the negative charge at amino acid 351 controls the estrogen-like action at activating function 2b of the selective estrogen receptor modulator ER␣ complex.Raloxifene (Ral) 1 (see Fig. 1) is a polyhydroxyphenyl benzothiophene antiestrogen that has low estrogen agonist activity in the rodent uterus (1). The compound originally referred to as Ly156758 or keoxifene was abandoned for development as a treatment for breast cancer (2), because its bioavailability was less than 2% administered dose (3). However, the recognition that raloxifene maintains bone density (4, 5) and inhibits mammary carcinogenesis in the rat (6, 7) illustrates the concept of selective estrogen receptor modulation. Raloxifene is used for the prevention of osteoporosis in postmenopausal women (8), and treatment is associated with a reduced incidence of breast cancer (9).Tamoxifen is the prototype selective estrogen receptor modulator (SERM) that is used clinically for the treatment and prevention of breast cancer (10, 11) with the ability to maintain bone density in postmenopausal women (12). However, tamoxifen therapy is also associated with estrogen-like effects in the uterus with an increased incidence of endometrial cancer (13). Raloxifene is currently being ...

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The oestrogen-like effect of 4-hydroxytamoxifen on induction of transforming growth factor alpha mRNA in MDA-MB-231 breast cancer cells stably expressing the oestrogen receptor

Cited by 52 publications

References 43 publications

Ionizing radiation modulates vascular endothelial growth factor (VEGF) expression through multiple mitogen activated protein kinase dependent pathways

Ionizing radiation modulates vascular endothelial growth factor (VEGF) expression through multiple mitogen activated protein kinase dependent pathways

Molecular classification of selective oestrogen receptor modulators on the basis of gene expression profiles of breast cancer cells expressing oestrogen receptor α

Structure-Function Relationships of the Raloxifene-Estrogen Receptor-α Complex for Regulating Transforming Growth Factor-α Expression in Breast Cancer Cells

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