Disease relevance of trans-Hydroxytamoxifen

• Antagonism by suramin of the growth-inhibitory effect of hydroxytamoxifen and doxorubicin in human MCF-7 breast cancer cells [1].
• The effects of trans-4-hydroxytamoxifen (OHTam) on proliferation of cells of the Ishikawa human endometrial adenocarcinoma line were studied under serum-free, phenol red-free conditions and compared to those of estradiol [2].
• Lipoprotein lipase in post-heparin plasma from postmenopausal patients with hypertriglyceridemia treated with or without tamoxifen was incubated with or without 4-hydroxy-tamoxifen (4-OHT), the monomers and dimers were separated on a heparin-Sepharose column and their masses were measured [3].
• Hydroxytamoxifen interaction with human erythrocyte membrane and induction of permeabilization and subsequent hemolysis [4].

High impact information on trans-Hydroxytamoxifen

• Estradiol (E2) or the antiestrogen hydroxytamoxifen is required for ER binding as assayed by gel retardation [5].
• Here we constructed Stat6:ER, a Stat6-estrogen receptor fusion protein that can be activated by 4-hydroxy-tamoxifen, independently of IL-4 and endogenous Stat6 [6].
• In the absence of 17 beta-estradiol, 3-hydroxytamoxifen gave rise to a moderate increase in the progesterone receptor levels, which demonstrates the partially estrogenic character of hydroxytamoxifen [7].
• Moreover, the oestrogen receptor (ER) AF-2 antagonist hydroxytamoxifen cannot promote ER-TIF1 interaction [8].
• A second binding site for hydroxytamoxifen within the coactivator-binding groove of estrogen receptor beta [9].

Chemical compound and disease context of trans-Hydroxytamoxifen

• Treatment of human breast cancer cytosol with tamoxifen (Tam) or 4-monohydroxytamoxifen (MHT) enhances the immunoreactivity of the estrogen receptor toward monoclonal antibody H222 but not monoclonal antibodies D547 or D75 [10].
• Ruthenocene derivatives act as anti-estrogens as effective (n = 2) or slightly more effective (n = 3-5) than hydroxytamoxifen on ERalpha-positive breast cancer cell lines but, unlike ferrocifens, do not show antiproliferative effects on ERalpha-negative breast cancer cell lines [11].
• The growth effects of tamoxifen (T), desmethyl-tamoxifen (dMeT), 4-hydroxy-tamoxifen (OHT) and enclomiphene (Clo) on cultured human breast cancer cell lines have been related to published binding affinities for the estrogen receptor [12].
• EM-652 was the most potent antiestrogen to inhibit the growth of human breast cancer ZR-75-1, MCF-7 and T-47D cells in vitro when compared with ICI 182780, ICI 164384, hydroxytamoxifen, and droloxifene [13].
• Antiestrogenic properties of keoxifene, trans-4-hydroxytamoxifen, and ICI 164384, a new steroidal antiestrogen, in ZR-75-1 human breast cancer cells [14].

Biological context of trans-Hydroxytamoxifen

• The antiestrogens tamoxifen and hydroxytamoxifen inhibit cell proliferation below the control level only when cells are grown in the presence of phenol red; in the absence of phenol red, the antiestrogens do not suppress growth [15].
• However, simultaneous treatment of cells expressing wild-type ER with trans-4-hydroxytamoxifen and dopamine resulted in transgene expression that was additive in nature compared to either compound alone; similar treatment of cells expressing [Val400]ER produced a synergistic increase [16].
• We now show that in hydroxytamoxifen-treated cells, transduction of the cell cycle inhibitor p27(Kip1) induces quiescence and insensitivity to growth stimulation by insulin/insulin-like growth factor I and epidermal growth factor/transforming growth factor alpha [17].
• Out of five estrogen conjugates, only 3-glucurono-estradiol partly suppressed the inhibition of hydroxytamoxifen; the conjugate also reduced the estrogen receptor content of the cells, probably by a down regulation process ("processing") [18].
• Long-term hydroxytamoxifen treatment of an MCF-7-derived breast cancer cell line irreversibly inhibits the expression of estrogenic genes through chromatin remodeling [19].

Anatomical context of trans-Hydroxytamoxifen

• This cell line allowed us to visualize the induction by hydroxytamoxifen of a heterogeneity in the cell population with regard to the expression of the luciferase gene [20].
• 4- Hydroxy-tamoxifen (4-OHT) increased ER-alpha and silencing mediator for retinoid and thyroid receptors (SMRT) expression and increased ER-ERE binding [21].
• Autocrine regulation of cell proliferation by estradiol and hydroxytamoxifen of transformed mouse Leydig cells in serum-free culture [22].
• Incubations with control, heat-treated microsomes resulted in approximately 1% isomerization of trans-4-hydroxytamoxifen [23].
• Similarly, only the highest concentration of hydroxytamoxifen (60 nmol/mg protein) affected the phosphorylative capacity of brain mitochondria, characterized by a decrease in the repolarization level and an increase in the repolarization lag phase [24].

Associations of trans-Hydroxytamoxifen with other chemical compounds

• The regulation of endogenous genes by E2 and 4-hydroxy-tamoxifen were measured in these cells using gene microarrays and real-time RT-PCR [25].
• Microsomal and peroxidase activation of 4-hydroxy-tamoxifen to form DNA adducts: comparison with DNA adducts formed in Sprague-Dawley rats treated with tamoxifen [26].
• The IC50 values were 35-45 microM for tamoxifen, 58-66 microM for clomiphene, and 88 microM for hydroxytamoxifen [27].
• Moreover, EM-652 and EM-800 have no stimulatory effect on the basal levels of cell proliferation in the absence of E2 while hydroxytamoxifen and droloxifene had a stimulatory effect on the basal growth of T-47D and ZR-75-1 cells [13].
• An important aspect of EM-652 is that it inhibits both the AF1 and AF2 functions of both ER alpha and ER beta while the inhibitory action of hydroxytamoxifen is limited to AF2, the ligand-dependent function of the estrogen receptors [13].

Gene context of trans-Hydroxytamoxifen

• We constructed an inducible MLL fusion, MLL-ENL-ERtm, that rendered the transcriptional and transforming properties of MLL-ENL strictly dependent on the presence of 4-hydroxy-tamoxifen [28].
• For this, MCF-7 cells stably transfected with a tet-inducible cyclin D1 expression vector were tested for their in vitro response to steroidal (ICI 182,780) and nonsteroidal (trans-4-hydroxytamoxifen) antiestrogens under condition of low (endogenous only) or high (exogenous) cyclin D1 levels [29].
• An estrogen-responsive element-targeted histone deacetylase enzyme has an antiestrogen activity that differs from that of hydroxytamoxifen [30].
• We have previously observed that QR is up-regulated by the antiestrogen trans-hydroxytamoxifen in breast cancer cells [31].
• Using a semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) assay, we demonstrated that both E2 and 4-hydroxy-tamoxifen (OHT) enhanced IGF-I expression but had no effect on IGF-II expression [32].

Analytical, diagnostic and therapeutic context of trans-Hydroxytamoxifen

• trans-4-Hydroxytamoxifen concentration and metabolism after local percutaneous administration to human breast [33].
• This apparently paradoxical behavior of cis-hydroxytamoxifen was shown to be due to the fact that the cis- and trans-hydroxytamoxifens readily undergo isomeric interconversion upon exposure to our cell culture conditions, resulting in substantial accumulation of the higher-affinity trans-hydroxytamoxifen in the nuclear ER fraction of cells [34].
• The time course of the early stage of estradiol-17 beta (E2) and hydroxytamoxifen (OHTAM) action at the plasma membrane of hormone-responsive MCF-7 and non-responsive MDA-MB-231 (MDA) breast cancer cell lines was investigated using scanning electron microscopy (SEM), electron probe X-ray microanalysis and microelectrophysiology analysis [35].
• Effect of treatment with hydroxytamoxifen (OH-Tam) on ER level in MCF-7 cells was investigated by an approach combining ER measurement (enzyme immunoassay) and morphological demonstration (immunofluorescence) [36].
• Flow cytometry analysis of the growth inhibitory effect of 4-hydroxy-tamoxifen on a human breast carcinoma cell line [37].

References