Supplementary Table 1 from Invasive Lobular Carcinoma Cell Lines Are Characterized by Unique Estrogen-Mediated Gene Expression Patterns and Altered Tamoxifen Response
Matthew J. SikoraKristine CooperAmir BahreiniSoumya LuthraGuoying WangUma ChandranNancy E. DavidsonDavid J. DabbsAlana L. WelmSteffi Oesterreich
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<p>XLSX file - 2042K, Lists for genes regulated by E2 in MM134 and SUM44 cells, and for categories of genes based on cell type specificity.</p>Keywords:
Carcinoma Cell
Tamoxifen dosage is based on the one-dose-fits-all approach. The anticancer effect of tamoxifen is believed to be due to the metabolites, 4-hydroxytamoxifen (4OHtam), and 4-hydroxy-N-desmethyltamoxifen (4OHNDtam/endoxifen). These demethylated metabolites of tamoxifen have been associated with its side effects, whereas the effect mediated by tamoxifen-N-oxide (tamNox) is still poorly understood. Our objective was to improve the therapeutic index of tamoxifen by personalizing its dosage and maintaining serum tamoxifen metabolite concentrations within a target range. We examined the levels of tamoxifen, 4OHtam, 4OHNDtam, N-desmethyltamoxifen (NDtam), N-desdimethyltamoxifen (NDDtam), and tamNox in serum and in breast tumors specimens of 115 patients treated with 1, 5 or 20 mg/day of tamoxifen for 4 weeks before surgery in a randomized trial. Furthermore, the metabolism of tamNox in MCF-7 breast cancer cells was also studied. The concentrations of tamoxifen and its metabolites in tumor tissues were significantly correlated to their serum levels. Tumor tissue levels were 5–10 times higher than those measured in serum, with the exception of tamNox. In MCF-7 cells, tamNox was converted back to tamoxifen. In contrast to the tissue distribution of tamNox, the concentrations of 4OHtam and 4OHNDtam in tumor tissues corresponded to their serum levels. The results suggest that implementation of therapeutic drug monitoring may improve the therapeutic index of tamoxifen. Furthermore, the tissue distribution of tamNox deviated from that of the other tamoxifen metabolites.
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A major challenge in cancer research is to discover drugs with high selectivity and minor side-effects. Tamoxifen has been widely used for more than 30 years in breast cancer treatment and prevention. Tamoxifen acts mainly via estrogen receptors (ER), but also displays anti-tumor activity in breast cancer negative to ERs, suggesting other targets. Actually, tamoxifen has effects on several transduction pathways and diverse ion channels. Despite the successful use of tamoxifen, this drug produces some non-desirable side-effects by acting on different targets. However, such nonspecificity of tamoxifen might be used to unravel new targets to inhibit tumor cell proliferation, to elucidate new mechanisms of action of tamoxifen and tamoxifen analogs, and finally, to design new more specific and potent drugs on the benefit of cancer patients. This review will briefly describe first the current and general aspects of tamoxifen and then will focus more deeply on various tamoxifen analogues and new uses of tamoxifen described in recent patents. We will describe the biological effects and the therapeutic targets of the new patented analogues, in order to offer an alternative panorama on tamoxifen-based chemotherapy. Keywords: Breast cancer, estrogen receptor, gene expression, ion channels, tamoxifen, tamoxifen derivatives, tamoxifen patents, Selective Estrogen Receptor Modulator, Triphenylethylenes, Benzothiophenes
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PURPOSE: Perioperative tamoxifen practices in microvascular breast reconstruction vary widely. However, no prior literature has investigated this issue from a national standpoint. Thus, this study investigated: (1) the impact of tamoxifen therapy on microvascular flap outcomes using nationwide data, and (2) amongst those on tamoxifen therapy, the impact of perioperative tamoxifen use on flap outcomes. METHODS: This was a retrospective cohort investigation using Truven MarketScan Databases (2014-2017). All women who underwent microvascular breast reconstruction were included; prescriptions claims data was used to identify those on tamoxifen. Outcomes were compared between tamoxifen/non-tamoxifen cohorts. Subgroup analyses in the tamoxifen cohort were undertaken to investigate whether perioperative tamoxifen use impacted outcomes. RESULTS: Overall, 5,832 women were included, of whom 1,983 (34%) were on tamoxifen. There were no differences in flap-related adverse events between tamoxifen and non-tamoxifen cohorts (OR: 1.00; 95%CI: 0.79-1.31; p=0.38). However, amongst patients determined to be at high risk for thrombotic complications, those on tamoxifen therapy had a significantly higher risk of 90-day postoperative venous thromboembolism (OR: 1.15; 95%CI: 1.01-1.28; p=0.04). There were no significant differences in flap failure between those who held tamoxifen versus those who continued tamoxifen into the perioperative period. CONCLUSION: Upon review of national data, preoperative tamoxifen therapy did not significantly increase flap complications/failure after microvascular breast reconstruction. However, patients on tamoxifen therapy with thrombotic risk factors as determined by the Caprini risk score were found to have greater risk for postoperative venous thromboembolism- such patients may need special consideration for postoperative chemoprophylaxis.
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