Targeting oestrogen to kill the cancer but not the patient

Lewis, Joan S.; Cheng, Dong; Jordan, V. Craig

doi:10.1038/sj.bjc.6601627

Cited by 24 publications

(21 citation statements)

References 26 publications

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“…Therefore, three results have been reached: 1) there is an urgent need to identify and develop a new generation of therapeutic agents and systemic therapies targeting the E 2 /ER signaling to avoid the treatment of unresponsive breast carcinomas (21); 2) further benefits of clinical trials for SERMs and/or AIs should include the study of predictive biomarkers of disease to provide insights into SERM-and AI-based therapy resistance and sensitivity; and 3) new information on the mechanisms of E 2 /ER function and/or cross talk with other prosurvival cascades should provide the basis for the development of other ideal anti-E 2 therapies with the intent to enhance clinical efficacy and reduce side effects or both.…”

Section: There Is An Urgent Need To Identify and Develop A New Generamentioning

confidence: 99%

Targeting Fatty Acid Synthase in Breast and Endometrial Cancer: An Alternative to Selective Estrogen Receptor Modulators?

2006

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There is an urgent need to identify and develop a new generation of therapeutic agents and systemic therapies targeting the estradiol (E2)/estrogen receptor (ER) signaling in breast cancer. In this regard, new information on the mechanisms of E2/ER function and/or cross talk with other prosurvival cascades should provide the basis for the development of other ideal anti-E2 therapies with the intent to enhance clinical efficacy, reduce side effects or both. Our very recent assessment of the mechanisms by which cancer-associated increased lipogenesis and its inhibition alters the E2/ER signaling discovered that fatty acid synthase (FASN), the enzyme catalyzing the terminal steps in the de novo biosynthesis of long-chain fatty acids, differentially modulates the state of sensitivity of breast and endometrial cancer cells to E2-stimulated ER transcriptional activation and E2-dependent cell growth and survival: 1) pharmacological inhibition of FASN activity induced a dramatic augmentation of E2-stimulated ER-driven gene transcription, whereas interference (RNAi)-mediated silencing of FAS gene expression drastically lowered E2 requirements for optimal activation of ER transcriptional activation in breast cancer cells; conversely, pharmacological and RNAi-induced inhibition of FASN worked as an antagonist of E2- and tamoxifen-dependent ER transcriptional activity in endometrial adenocarcinoma cells; 2) pharmacological and RNAi-induced inhibition of FASN synergistically enhanced E2-mediated down-regulation of ER protein and mRNA expression in breast cancer cells, whereas specific FASN blockade resulted in a marked down-regulation of E2-stimulated ER expression in endometrial cancer cells; and 3) FASN inhibition decreased cell proliferation and cell viability by promoting apoptosis in hormone-dependent breast and endometrial cancer cells. In this review we propose that, through a complex mechanism involving the regulation of MAPK/ER cross talk as well as critical E2-related proteins including the Her-2/neu (erbB-2) oncogene and the cyclin-dependent kinase inhibitors p21(WAF1/CIP1) and p27(Kip1), a previously unrevealed connection exists between FASN and the genomic and nongenomic ER activities in breast and endometrial cancer cells. From a clinical perspective, we suggest that if chemically stable FASN inhibitors or cell-selective systems able to deliver RNAi targeting FASN gene demonstrate systemic anticancer effects of FASN inhibition in vivo, additional preclinical studies to characterize their anti-breast cancer actions should be of great interest as the specific blockade of FASN activity may also provide a protective means against endometrial carcinoma associated with tamoxifen-based breast cancer therapy.

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Section: There Is An Urgent Need To Identify and Develop A New Generamentioning

confidence: 99%

Targeting Fatty Acid Synthase in Breast and Endometrial Cancer: An Alternative to Selective Estrogen Receptor Modulators?

2006

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“…Resistance to tamoxifen, in the form of tamoxifenstimulated growth, has been well documented in the laboratory and in the clinic [7,18,19], however, recent evidence suggests the emergence of a new form of drug resistance that develops after many years of selective estrogen receptor modulator (SERM) therapy [20]. Rather than estrogen stimulating growth, the cells become supersensitized to the effects of physiologic levels of E 2 , which causes apoptosis and rapid tumor regression [21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Estrogen-induced apoptosis in a breast cancer model resistant to long-term estrogen withdrawal

Lewis

Osipo

Meeke

et al. 2005

The Journal of Steroid Biochemistry and Molecular Biology

116

110

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“…However, the consequence of long term TAM therapy is drug resistance (10, 11). Although, resistance to TAM has been well documented (10, 12, 13), evidence suggests the emergence of a new form of drug resistance that develops after many years of selective estrogen receptor modulator therapy (14). A recent study showed that TAM-resistant breast cancer can be reversed by the use of low doses of E2 for a short period of time to resensitize ER␣-positive tumors again to the growth inhibitory effects of antiestrogens (15).…”

mentioning

confidence: 99%

Tamoxifen and Estradiol Interact with the Flavin Mononucleotide Site of Complex I Leading to Mitochondrial Failure

Moreira

Custódio

Moreno

et al. 2006

Journal of Biological Chemistry

120

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This study evaluated the action of tamoxifen and estradiol on the function of isolated liver mitochondria. We observed that although tamoxifen and estradiol per se did not affect mitochondrial complexes II, III, or IV, complex I is affected, this effect being more drastic (except for state 4 of respiration) when mitochondria were coincubated with both drugs. Furthermore, using two respiratory chain inhibitors, rotenone and diphenyliodonium chloride, we identified the flavin mononucleotide site of complex I as the target of tamoxifen and/or estradiol action(s). Tamoxifen (25 M) per se induced a significant increase in hydrogen peroxide production and state 4 of respiration. Additionally, a significant decrease in respiratory control ratio, transmembrane, and depolarization potentials were observed. Estradiol per se decreased carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP)-stimulated respiration, state 3 of respiration, and respiratory control ratio and increased lag phase of repolarization. With the exception of state 4 of respiration whose increase induced by tamoxifen was reversed by the presence of estradiol, the effects of tamoxifen were highly exacerbated when estradiol was present. We observed that 10 M tamoxifen in the presence of estradiol affected mitochondria significantly by decreasing FCCP-stimulated respiration, state 3 of respiration, respiratory control ratio, and ADP depolarization and increasing the lag phase of repolarization. All of the deleterious effects induced by 25 M tamoxifen were highly exacerbated in the presence of estradiol. Furthermore, we observed that the effects of both compounds were independent of estrogen receptors because the pure estrogen antagonist ICI 182,780 did not interfere with tamoxifen and/or estradiol detrimental effects. Altogether, our data provide a mechanistic explanation for the multiple cytotoxic effects of tamoxifen including its capacity to destroy tamoxifen-resistant breast cancer cells in the presence of estradiol. This new piece of information provides a basis for the development of new and promising anticancer therapeutic strategies.Selective estrogen receptor modulators, also known as tissue selective estrogens, are a class of drugs with mixed estrogen agonist/antagonist actions (1). They were originally classified as antiestrogens because of their ability to antagonize the proliferative effects of estrogens (2). It was later discovered that these compounds could antagonize the action of estrogen by binding to the estrogen receptor (ER) 2 to thereby block estradiol (E2) access (1, 3). It is now known that under certain circumstances and in certain tissues, in addition to acting as competitive inhibitors of endogenous estrogen, these same estrogen antagonists can exert estrogenic agonist properties (4 -6). These findings indicate that the mechanisms regulating ER function are not the same in all cells and that a compound can only be classified as an ER agonist or antagonist in relation to a specific cell type or process.It is known for a long ti...

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Targeting oestrogen to kill the cancer but not the patient

Cited by 24 publications

References 26 publications

Targeting Fatty Acid Synthase in Breast and Endometrial Cancer: An Alternative to Selective Estrogen Receptor Modulators?

Targeting Fatty Acid Synthase in Breast and Endometrial Cancer: An Alternative to Selective Estrogen Receptor Modulators?

Estrogen-induced apoptosis in a breast cancer model resistant to long-term estrogen withdrawal

Tamoxifen and Estradiol Interact with the Flavin Mononucleotide Site of Complex I Leading to Mitochondrial Failure

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