The Effect of Raloxifene on Risk of Breast Cancer in Postmenopausal Women: Results From the MORE Randomized Trial

Cummings, Steven R.; Eckert, Stephen; Krueger, Kathryn A.; Grady, Deborah; Powles, Trevor J.; Cauley, Jane A.; Norton, Larry; Nickelsen, Thomas; Bjarnason, Nina H.; Morrow, Monica; Lippman, Marc E.; Black, Dennis M.; Glusman, J. E.; Costa, Alberto; Jordan, V. Craig

doi:10.1097/00006254-200002000-00023

Cited by 460 publications

(669 citation statements)

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“…The antioestrogen tamoxifen has oestrogenic activities in the bone, uterus and the cardiovascular system (Bagdade et al, 1990;Ryan et al, 1991;Love et al, 1994;Barrett-Connor et al, 1999) and is an anti-oestrogenic in the breast (Jordan, 2000;Morrow and Jordan, 2000). Raloxifene (Ral), on the other hand, has less oestrogenic effects on uterus, but the same beneficial effects on bone and lipid metabolism (Delmas et al, 1997;Barrett-Connor et al, 1999;Cohen et al, 2000) while it is an antagonist of oestrogen action in the breast (Gottardis and Jordan, 1987;Cummings et al, 1999). Other SERMs like idoxifene (Idox) (Chander et al, 1991;Nuttall et al, 1998), GW 5638 (Willson et al, 1994(Willson et al, , 1997Connor et al, 2001) and EM 800 (Luo et al, 1998;Labrie et al, 1999;Martel et al, 2000) are different from tamoxifen and based on their activity in the rodent uterus are more closely related to raloxifene.…”

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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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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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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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“…[26][27][28] Endocrine therapy using anti-estrogens or aromatase inhibitors is the most common and most effective treatment for ERa-positive breast cancer; however, many tumors tend to acquire resistance to estrogen during the course of this therapy. [29][30][31] ERa-negative breast cancers are originally resistant to endocrine therapy. 32 We have also revealed that Efp is expressed in 70% of breast cancer specimens.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of Efp by DNA-modified small interfering RNA inhibits breast cancer cell proliferation and in vivo tumor growth

et al. 2010

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The estrogen-responsive gene Efp promotes the growth of breast cancer cells by stimulating the degradation of a negative cell-cycle regulator, 14-3-3s, and is hence considered a suitable molecular target for breast cancer therapy. The use of small interfering RNA (siRNA) and its derivatives to silence cancer-related genes is being investigated with the aim of identifying clinical applications for these molecules. Recently, it has been shown that DNA-modified siRNA (chimeric siRNA) has good potential in clinical applications, because it induces fewer off-target effects or immune responses in mammalian cells. In the present study, we identified the most specific and effective siRNA (siEfp-1) for silencing Efp expression in MCF-7 breast cancer cells. For this purpose, we used an algorithm that primarily eliminates off-target effects. siEfp-1 considerably suppressed the in vitro proliferation and cell-cycle progression of MCF-7 cells, as well as the in vivo growth of MCF-7 tumors, in athymic mice. DNA-modified siEfp-1 (chimeric siEfp) significantly inhibited the expression of Efp, proliferation of cultured cells and the in vivo growth of MCF-7-derived tumors in athymic mice. In addition, the silencing of Efp expression by siEfp-1 and chimeric siEfp increased the expression of the 14-3-3s protein. These results suggest that siEfp-1 and chimeric siEfp could be useful in breast cancer therapy. Chimeric siEfp, in particular, has a high specificity and induces few side effects and is therefore expected to be used as a novel nucleic acid-based therapeutic agent.

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“…[131,132]. The anticipated result in reducing the risk of breast cancer as a beneficial side effect of treating osteoporosis propelled raloxifene into clinical trial vs. tamoxifen for the prevention of breast cancer as the primary endpoint.…”

Section: Selective Estrogen Receptor Modulation and Chemopreventionmentioning

confidence: 99%

“…A use patent for the treatment and prevention of osteoporosis was filed by Eli Lilly in 1992. Raloxifene has now been available for the treatment and prevention of osteoporosis in postmenopausal women since 1999 based on the prospective clinical trials demonstrating an approximately 40% decrease in spinal fractures [130] with the advantage over hormone replacement therapy of causing a 70% decrease in the incidence of breast cancer [131,132]. The anticipated result in reducing the risk of breast cancer as a beneficial side effect of treating osteoporosis propelled raloxifene into clinical trial vs. tamoxifen for the prevention of breast cancer as the primary endpoint.…”

Section: Selective Estrogen Receptor Modulation and Chemopreventionmentioning

confidence: 99%

Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer

Jordan¹,

Brodie²

2007

Steroids

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259

183

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The enthusiasm with which the clinical community has embraced the use of antiestrogenic therapy to treat breast cancer is based upon the proven record of success that first the nonsteroidal antiestrogen tamoxifen and then the aromatase inhibitor have demonstrated in clinical trial. The reasons for the enthusiasm are obvious. Antihormonal therapy, particularly aromatase inhibition to create a "no estrogen state" in the postmenopausal breast cancer patient is effective, saves women's lives, is contributing successfully to reducing the national mortality from breast cancer, is relatively cheap and has fewer side effects and easy administration (oral) than any other anticancer strategy. However, the successful application of a therapeutic strategy to block the known growth stimulation property of estrogen in breast cancer was not greeted with such enthusiasm 40 years ago.Estrogen is essential for life. Without the critical role of estrogenic steroids, reproduction would not be possible. Based on emerging knowledge from laboratory studies, the value of modulating the steroid environment during the menstrual cycle was advanced to clinical testing during the 1950's as a means of oral contraception. The results of these studies were to change society forever.The Worcester Foundation for Experimental Biology is the place where Gregory Pincus established the scientific principles necessary to propose clinical testing of the oral contraceptive and M.C. Chang subsequently established the first protocols to perform in vitro fertilization. Simply stated, the Worcester Foundation was, at that time, the world center for steroid endocrinology and reproductive biology. Over the years, hundreds of scientists have trained at the Foundation and subsequently spread their knowledge throughout the world [1]. However, fashions in research change and new opportunities emerge.In 1971, President Nixon made a national commitment to seek a cure for cancer by signing the National Cancer Act. Mahlon Hoagland, the President of the Worcester Foundation, responded to the initiative by appointing Professor Elwood V. Jensen, Director of the Ben May Cancer Research Laboratory at the University of Chicago, to be a member of the Foundation's Scientific Advisory Board. Jensen had discovered the estrogen receptor (ER) as the putative mechanism of estrogen action in its target tissues [2]. The known link between estrogen and breast cancer suggested that "antiestrogenic strategies" might have potential as therapeutic Correspondence to: V. Craig Jordan, v.craig.jordan@fccc.edu. Present Address: Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be d...

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The Effect of Raloxifene on Risk of Breast Cancer in Postmenopausal Women: Results From the MORE Randomized Trial

Cited by 460 publications

References 0 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

Knockdown of Efp by DNA-modified small interfering RNA inhibits breast cancer cell proliferation and in vivo tumor growth

Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer

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