Agonist activity of antiestrogen-receptor complexes to regulate urokinase plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) endogenous gene expression in breast cancer cells

Levenson, Anait S.; Svoboda, K. M.; Kwaan, Hau C.; Jordan, V. Craig

doi:10.1016/s0304-3835(97)00516-8

Cited by 15 publications

(14 citation statements)

References 13 publications

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“…Our previous classification of SERMs in these two cell lines was based on one single marker of E2-responsiveness in these breast cancer cells: E2 and 4OHT produced oestrogenic effects on the activation of TGFa mRNA in cell expressing wtERa whereas Ral and ICI were anti-oestrogens (Levenson et al, 1998b). With the mutant receptor, Ral became oestrogenic as well (Levenson et al, 1997;Levenson and Jordan, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…We chose a well characterised model system in vitro in which cellular machinery is adapted for ERnonmediated transcription of genes (MDA-MB-231 cells), and (Levenson et al, 1997(Levenson et al, , 1998b(Levenson et al, ,c, 2001Levenson and Jordan, 1998;MacGregor Schafer et al, 1999) in these cells. Different analytical tools have been proposed for analysing microarray data (Eisen et al, 1998;Golub et al, 1999;Kalocsai and Shams, 2001;Tamayo et al, 1999;Toronen et al, 1999;Bittner et al, 2000).…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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“…Amino acid 351 is important for SERM activity and upon point mutation (D351Y) renders the receptor responsive to tamoxifen [28,29,72]. Given the disparate response to ligand of this tumor-derived ER mutant compared to wtERa, we examined the ability of BPA and COU to stimulate receptor activity using the 3ÂERE/TAT-Luc reporter construct as a read out for transcriptional activation.…”

Section: Bpa and Cou Elicit Disparate Responses In Tumor-derived Er Mmentioning

confidence: 99%

Xenoestrogen action in breast cancer: impact on ER-dependent transcription and mitogenesis

Hess-Wilson

Boldison

Weaver

et al. 2005

Breast Cancer Res Treat

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Several estrogen mimics (xenoestrogens) inappropriately activate the estrogen receptor (ER) in the absence of endogenous ligand. Given the importance of the ER in breast cancer growth and regulation, delineating the impact of these agents under conditions related to tumor treatment is of significant importance. We examined the effect of two prevalent xenoestrogens (bisphenol A and coumestrol) on ER activation and ER-dependent mitogenesis in breast cancer cells. We show that the ability of these agents to induce mitogenesis was restricted to conditions of estrogen depletion, and that these agents failed to cooperate with estradiol to induce MCF-7 breast cancer cell growth. These observations are consistent with the impact of each agent specifically on exogenous ER activation as monitored in HeLa cells, wherein the xenoestrogens activated the receptor in the absence of estradiol but failed to cooperate with estrogen. Tamoxifen blocked bisphenol A and coumestrol-mediated ER activation, indicating that exposure to these agents is unlikely to disrupt such therapeutic intervention. The response of tumor-derived ER alleles to these xenoestrogens was also examined. Although the xenoestrogens failed to alter ER-Y537S function, the ER-D351Y mutant demonstrated an enhanced response to bisphenol A. Moreover, tamoxifen enhanced the agonistic effects of xenoestrogens on ER-D351Y. Lastly, we examined the impact of ER co-activator overexpression on xenoestrogen response. Bisphenol A and coumestrol exhibited differential responses to co-activators with regard to ER activation. However, when using mitogenesis as an endpoint, these co-activators were insufficient to provide a significant growth advantage. Combined, these data demonstrate that bisphenol A and coumestrol can impact ER activity and ER-dependent proliferation in breast cancer cells, but the influence of these agents is restricted to conditions of estrogen depletion, selective mutation of the ER, and expression of specific co-activators.

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“…Both ER-positive and ER-negative breast cancer cells and breast tumor fibroblasts can express and release uPA, uPAR, and PAI-1 under in vitro conditions (33)(34)(35)(36)(37)(38)(39). In recent years, the significance of uPA and uPAR in invasion and metastases of hormone-dependent cancers (e.g., breast and prostate) has been demonstrated (40,41).…”

Section: Discussionmentioning

confidence: 99%

“…In recent years, the significance of uPA and uPAR in invasion and metastases of hormone-dependent cancers (e.g., breast and prostate) has been demonstrated (40,41). uPA and PAI-1 expression have been shown to be regulated by estradiol and antiestrogens via an ER-mediated pathway (35)(36)(37), whereas uPAR expression was not affected (35). Because of the observed up-and down-regulation of the expression and secretion of the factors of the uPA system by various growth factors in breast fibroblasts in vitro (38, 39, 42, 43) and the capability of uPA and uPAR to promote epithelial tumor cell proliferation directly (44) or indirectly through activation or release of growth factors, it is tempting to speculate that in the microenvironment of a tumor, the serine protease uPA may interfere with the efficacy of tamoxifen treatment in patients with (recurrent) breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Urokinase-Type Plasminogen Activator System in Breast Cancer

et al. 2004

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The prognostic value of components of the urokinase-type plasminogen activator (uPA) system, its receptor uPAR (CD87), and plasminogen activator inhibitors PAI-1 and PAI-2 is well established. We studied the predictive value of these proteolytic factors by evaluating the association of their tumor expression level and the efficacy of tamoxifen therapy in patients with recurrent breast cancer. The antigen levels of the four factors were determined by ELISA in cytosols prepared from estrogen receptor-positive primary breast tumors of 691 hormone-naive breast cancer patients with recurrent disease and treated with tamoxifen as first-line systemic therapy. High tumor levels of uPA (P < 0.001), uPAR (P < 0.01), and PAI-1 (P ‫؍‬ 0.01) were associated with a lower efficacy of tamoxifen therapy. In the multivariable analysis, uPA (P < 0.001) provided additional information independent of the traditional predictive factors to predict benefit from tamoxifen therapy. High levels of uPA, uPAR, and PAI-1 predicted a shorter progression-free survival (PFS) on tamoxifen in an analysis of the first 9 months of therapy. However in the analysis during the total follow-up period, high PAI-2 levels (P ‫؍‬ 0.01) showed a longer response to tamoxifen. In conclusion, uPA, uPAR, and PAI-1, components of the urokinase system, are predictive for the efficacy of tamoxifen therapy in patients treated for recurrent breast cancer. Knowledge of their tumor expression levels might be helpful for future individualized therapy protocols, including possible new-targeted therapies based on the interference in the urokinase system.

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Agonist activity of antiestrogen-receptor complexes to regulate urokinase plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) endogenous gene expression in breast cancer cells

Cited by 15 publications

References 13 publications

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

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

Xenoestrogen action in breast cancer: impact on ER-dependent transcription and mitogenesis

Urokinase-Type Plasminogen Activator System in Breast Cancer

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