Therapeutic Strategies Using the Aromatase Inhibitor Letrozole and Tamoxifen in a Breast Cancer Model

Long, Brian J.; Jelovac, Danijela; Handratta, Venkatesh; Thiantanawat, Apinya; Macpherson, Nicol; Ragaz, Joseph; Goloubeva, Olga; Brodie, Angela

doi:10.1093/jnci/djh076

Cited by 113 publications

(138 citation statements)

References 25 publications

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“…The possibility that blockade of estrogen action and estrogen synthesis may be synergistic was explored by treating mice with the aromatase inhibitor letrozole and the antiestrogen tamoxifen alone and in combination. However, the results in the model indicated that letrozole alone was better than tamoxifen or combined treatments [93]. This result was analogous to results later reported for the ATAC trial [94].…”

Section: Adjuvant Therapy With Tamoxifensupporting

confidence: 87%

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

Jordan¹,

Brodie²

2007

Steroids

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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Section: Adjuvant Therapy With Tamoxifensupporting

confidence: 87%

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

Jordan¹,

Brodie²

2007

Steroids

259

183

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“…MCF-7Ca tumors of mice treated with letrozole initially regressed but gradually resumed growth and had doubled in volume by week 21 of treatment (Brodie et al 2005). Interestingly, it was found that letrozole-resistant tumors did not respond to either tamoxifen or fulvestrant as second-line therapy (Long et al 2004a). These findings are in apparent contrast with the abovementioned reports from LTED in vitro experiments that suggested activity of fulvestrant in cells that had undergone adaptive supersensitivity, a condition that in vitro resembles resistance to AIs .…”

Section: Adaptation To Estrogen Withdrawalmentioning

confidence: 77%

“…The phenomenon of acquired resistance to AIs has also recently been addressed by using MCF-7 cells stably transfected with human aromatase gene (MCF7Ca) (Long et al 2004a, Brodie et al 2005. MCF-7Ca tumors of mice treated with letrozole initially regressed but gradually resumed growth and had doubled in volume by week 21 of treatment (Brodie et al 2005).…”

Section: Adaptation To Estrogen Withdrawalmentioning

confidence: 99%

Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer

Normanno

Maïo

Maio

et al. 2005

Endocr Relat Cancer

257

224

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Tamoxifen has been the mainstay of hormonal therapy in both early and advanced breast cancer patients for approximately three decades. The availability of novel compounds such as aromatase inhibitors (AIs) and fulvestrant, with different mechanism of action, is changing the scenario of endocrine treatment of postmenopausal breast cancer patients. In this review article, we have summarized the current knowledge of the mechanisms of resistance to endocrine therapy, in order to derive information that might be useful for therapeutic intervention. We propose that resistance to endocrine therapy is a progressive, step-wise phenomenon induced by the selective pressure of hormonal agents, which leads breast cancer cells from an estrogen-dependent, responsive to endocrine manipulation phenotype to a non-responsive phenotype, and eventually to an estrogenindependent phenotype. In particular, evidence suggests for each 'action' introduced to block estrogen stimulation of breast cancer cells (i.e. treatment with anti-estrogen), there are one or more corresponding 'reactions' that tumor cells can use to escape our attempts to block their growth: estrogen hypersensitivity associated with increased transcriptional activity of estrogen receptor a (ERa) and/or increased non-genomic activity of ERa, estrogen supersensitivity, increased growth factor signaling, suppression of ERa expression and finally estrogen independence. Activation of growth factor signaling is involved in each step of this phenomenon, and might ultimately substitute estrogen in sustaining the growth and the survival of breast cancer cells. In this respect, results of pre-clinical and clinical studies with AIs, fulvestrant and signaling inhibitors sustain this hypothesis. More importantly, the knowledge of the mechanisms involved in the resistance of breast cancer cells to endocrine therapy offers potential for novel therapeutic strategies.

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“…Mice were than injected s.c. daily with the indicated agents: 100 mg per mouse per day (5 Â weekly) plus 10 mg per mouse per day (5 Â weekly) of letrozole or 200 mg per mouse per day (5 Â weekly) of anastrozole and 20 mg kg À1 day À1 (5 Â weekly) of VN/14-1. The doses of letrozole, anastrozole, androstendione and VN/14-1 used are as determined previously (Long et al, 2002(Long et al, , 2004Patel et al, 2004). The mice were treated for the indicated times, after which they were killed by decapitation and blood collected.…”

Section: In Vivo Antitumour Studiesmentioning

confidence: 99%

Novel retinoic acid metabolism blocking agents have potent inhibitory activities on human breast cancer cells and tumour growth

et al. 2007

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Antitumour effects of retinoids are attributed to their influence on cell proliferation, differentiation, apoptosis and angiogenesis. In our effort to develop useful agents for breast cancer therapy, we evaluated the effects of four representative retinoic acid metabolism blocking agents (RAMBAs, VN/14-1, VN/50-1, VN/66-1 and VN/69-1) on growth inhibition of oestrogen receptor positive (ER þ ve, MCF-7 and T-47D) and oestrogen receptor negative (ER Àve, MDA-MB-231) human breast cancer cells. Additionally, we investigated the biological effects/molecular mechanism(s) underlying their growth inhibitory properties as well as their antitumour efficacies against MCF-7 and MCF-7Ca tumour xenografts in nude mice. We also assessed the effect of combining VN/14-1 and all-trans-retinoic acid (ATRA) on MCF-7 tumuor xenografts. The ER þ ve cell lines were more sensitive (IC 50 values between 3.0 and 609 nM) to the RAMBAs than the ER Àve MDA-MB-231 cell line (IC 50 ¼ 5.6 -24.0 mM). Retinoic acid metabolism blocking agents induced cell differentiation as determined by increased expression of cytokeratin 8/18 and oestrogen receptor-a (ER-a). Similar to ATRA, they also induced apoptosis via activation of caspase 9. Cell cycle analysis indicated that RAMBAs arrested cells in the G1 and G2/M phases and caused significant downregulation (480%) of cyclin D1 protein. In vivo, the growth of MCF-7 mammary tumours was dose-dependently and significantly inhibited (92.6%, Po0.0005) by VN/14-1. The combination of VN/14-1 and ATRA also inhibited MCF-7 breast tumour growth in vivo (up to 120%) as compared with single agents (Po0.025). VN/14-1 was also very effective in preventing the formation of MCF-7Ca tumours and it significantly inhibited the growth of established MCF-7Ca tumours, being as effective as the clinically used aromatase inhibitors, anastrozole and letrozole. Decrease in cyclin D1 and upregulation of cytokeratins, Bad and Bax with VN/14-1 may be responsible for the efficacy of this compound in inhibiting breast cancer cell growth in vitro and in vivo. Our results suggest that our RAMBAs, especially VN/14-1 may be useful novel therapy for breast cancer.

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Therapeutic Strategies Using the Aromatase Inhibitor Letrozole and Tamoxifen in a Breast Cancer Model

Abstract: First-line letrozole therapy extends time for tumor progression in this model relative to the other treatment regimens tested. However, further studies are needed to determine the most effective second-line therapy for tumors that progress on letrozole.

Cited by 113 publications

References 25 publications

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

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

Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer

Novel retinoic acid metabolism blocking agents have potent inhibitory activities on human breast cancer cells and tumour growth

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