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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The synethesis of a new retinoid, N-(4-hydroxyphenyl)-all-trans-retinamide, which has useful biological properties, is described. This retinoid was more potent than retinyl acetate in reversing keratinization caused by retinoid deficiency in tracheal organ culture. It was markedly less toxic than retinyl acetate when fed p.o. to rats over 2-week or 6-month periods. It was an effective agent for inhibition of the development of breast cancer induced in rats by N-nitroso-N-methylurea, although it was not as potent as retinyl acetate in this regard. However, the lesser toxicity of 4-hydroxyphenylretinamide makes it a superior agent for prevention of breast cancer. High-pressure liquid chromatographic analyses of liver and breast extracts from rats treated for 6 months with retinoids show the pharmacokinetic basis for the superiority of 4-hydroxyphenylretinamide; this retinoid and its metabolites were found in high concentrations in breast tissue, without any measurable accumulation in the liver or evident liver toxicity. In contrast, chronic feeding of retinyl acetate caused marked deposition of retinyl esters in the liver and severe hepatotoxicity. Whole mounts of rat mammary glands, made after chronic feeding of 4-hydroxyphenylretinamide, showed that it had a marked antiproliferative effect on mammary epithelium.
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PMID:N-(4-Hydroxyphenyl)retinamide, a new retinoid for prevention of breast cancer in the rat. 42 Dec 18

Liarozole is a new imidazole derivative with antitumoral properties. Effects of the compound alone and in combination with all-trans-retinoic acid on proliferation of MCF-7 human breast cancer cells were examined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay. Following 9 days of drug exposure, MCF-7 cell growth was concentration dependently inhibited by all-trans-retinoic acid (drug concentration resulting in 50% growth inhibition, 2 x 10(-8) M), while liarozole at 10(-5) M inhibited cell growth by only 35%. When MCF-7 cells were incubated with a combination of all-trans-retinoic acid and liarozole, the antiproliferative effect of all-trans-retinoic acid was clearly enhanced. This enhancement was dependent on the liarozole concentration and was more than 10-fold. A combination of 10(-8) M all-trans-retinoic acid and 10(-6) M liarozole resulted in a greater antiproliferative effect than that obtained with 10(-7) M all-trans-retinoic acid alone. When MCF-7 cells were incubated for 4 h with [3H]all-trans-retinoic acid, the radioactivity in the supernatant consisted of unaltered retinoid. However, when cells had been pretreated with 10(-6) M all-trans-retinoic acid overnight, they were able to substantially metabolize [3H]all-trans-retinoic acid during a subsequent 4-h incubation. High-performance liquid chromatography analysis of the supernatants revealed that the reaction products consisted mainly of very polar metabolites. Liarozole inhibited the metabolism of all-trans-retinoic acid in MCF-7 cells with 10(-5) M liarozole reducing the amount of polar metabolites by 87%. It is concluded that the enhancement by liarozole of the antiproliferative effects of retinoic acid on MCF-7 human breast cancer cells is probably due to inhibition of retinoic acid metabolism. Further research into these effects in MCF-7 cells as well as in other cancer cell lines will provide more information concerning the exact mechanism of action of liarozole and the use of inhibitors of retinoid metabolism in cancer treatment.
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PMID:Effects of liarozole, a new antitumoral compound, on retinoic acid-induced inhibition of cell growth and on retinoic acid metabolism in MCF-7 human breast cancer cells. 158 97

We studied the effects of all-trans retinoic acid (RA) combined with X-irradiation on confluent cultures of human breast cancer (MCF-7) and melanoma (C-143) cell lines, as well as in a normal human diploid fibroblast strain (AG 1522). RA in non-cytotoxic concentrations was a potent inhibitor of confluent holding recovery of potentially lethal damage (PLD repair) for all three cell types. A complete inhibition of recovery was observed at lower RA concentrations in the tumor lines than in the fibroblast strain. Exposure to RA prior to and during irradiation resulted in a radiosensitizing effect that was similar in MCF-7 and AG 1522 cells. The implications of these findings are discussed in terms of the potential value of retinoids as biological response modifiers for the clinical radiotherapy of cancer.
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PMID:Modification of radiosensitivity and recovery from X ray damage in vitro by retinoic acid. 271 81

The ability of all-trans-retinoic acid, 13-cis-retinoic acid, the free acid of etretinate (RO 10-1670), the 'arotinoid' RO 13-6298 and its free acid RO 13-7410 to affect the growth of T47D human breast cancer cells in vitro was investigated. The growth of T47D cells was inhibited by all of the retinoids tested, with the arotinoids being up to 100 times more effective than all-trans-retinoic acid. The presence of cellular retinoic acid binding protein (cRABP) was indicated by the cellular uptake of [3H]all-trans-retinoic acid. Maximum binding was 460 fmol/micrograms DNA. All of the retinoids with a polar terminal free carboxyl group readily competed for the binding sites, but none of the retinoids competed for the estrogen or progesterone receptor. Co-treatment of the T47D cells with 0.1 microM all-trans-retinoic acid and either tamoxifen (1 microM) or hydroxytamoxifen (10 nM or 0.1 microM) produced an additive effect on growth inhibition. No such additive effect was observed when T47D cells were co-treated with arotinoids and antiestrogens. The results showed that the T47D cells can serve as a useful model in vitro to test the effects of the synthetic retinoids and antiestrogens on steroid receptor-positive human breast cancer.
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PMID:The effects of retinoid treatment and antiestrogens on the growth of T47D human breast cancer cells. 300 57

Certain retinoids serve as effective chemopreventive agents against breast cancer. The effective retinoids are also antiproliferative agents for the mammary gland both in vivo and in vitro. N-(4-hydroxyphenyl)retinamide (HPR) can inhibit the occurrence of hyperplastic alveolar nodules in C3H mice in vivo and 7,12-dimethylbenz[a]anthracene-induced nodule-like alveolar lesions in vitro. Moreover, HPR can also inhibit the phorbol ester-induced promotion of hyperplastic alveolar nodule development in vitro. HPR is metabolized by the mammary gland in vitro and one of the metabolites competes for the cytosolic retinoic acid-binding protein although the metabolite is not all-trans-retinoic acid.
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PMID:Retinoids and mammary gland differentiation. 389 99

Retinoid response pathways involve retinoic acid receptors (RARs) and retinoid X receptors. N-(4-hydroxyphenyl) retinamide (4-HPR), a derivative of all-trans-retinoic acid (RA) is currently in clinical trials as a chemopreventive agent for breast cancer. The issue whether 4-HPR mediates its biological actions via classical retinoid receptor pathways remains to be investigated. In this study, we provide several lines of evidence that 4-HPR mediates its biological actions via a novel pathway(s) that does not involve the classical retinoid receptor pathways. For example, 4-HPR was more potent than RA as an antiproliferative agent and inhibited growth of otherwise RA-resistant human breast carcinoma cells. Exposure to 4-HPR resulted in the generation of DNA fragmentation with subsequent cell death in both RA-positive estrogen receptor (ER)-positive as well as RA-refractory ER-negative breast carcinoma cell lines. N-(4-Methoxyphenyl)retinamide (4-MPR), which is the major 4-HPR metabolite in circulation, was biologically inert in this system. 4-HPR and 4-MPR bound poorly to the RAR alpha, beta and gamma in vitro and only minimally activated the retinoic acid receptor element (RARE) and retinoid X receptor response elements (RXREs) in human breast carcinoma cells. Neither 4-HPR nor 4-MPR are metabolized to any of the known conventional retinoids. In addition, 4-HPR or 4-MPR transactivation of RAREs or RXREs transfected into MCF-7 and MDA-MB-231 cells was not noted at 48 h. Nevertheless 4-HPR-mediated cell death was observed at 48 h, further suggesting that neither 4-HPR nor 4-MPR are metabolized to retinoids which activate the RAREs or RXREs in breast carcinoma cells. Furthermore, unlike RA, which exhibited anti-AP1 activity, 4-HPR inhibition of growth did not involve anti-AP1 activity. These results suggest that 4-HPR acts by a unique pathway that is not mediated by retinoid receptors.
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PMID:N-(4-hydroxyphenyl)retinamide (4-HPR)-mediated biological actions involve retinoid receptor-independent pathways in human breast carcinoma. 758 55

The lactoferrin gene is highly expressed in many different tissues, and its expression is controlled by different regulators. In this report, we have defined a retinoic acid response element (RARE) in the 5'-flanking region of the lactoferrin gene promoter. The lactoferrin-RARE is composed of two AGGTCA-like motifs arranged as a direct repeat with 1-bp spacing (DR-1). A gel retardation assay demonstrated that it bound strongly with retinoid X receptor (RXR) homodimers and RXR-retinoic acid receptor (RAR) heterodimers as well as chicken ovalbumin upstream promoter transcription factor (COUP-TF) orphan receptor. In CV-1 cells, the lactoferrin-RARE linked with a heterologous thymidine kinase promoter was strongly activated by RXR homodimers in response to 9-cis-retinoic acid (9-cis-RA) but not to all-trans-RA. When the COUP-TF orphan receptor was cotransfected, the 9-cis-RA-induced RXR homodimer activity was strongly repressed. A unique feature of the lactoferrin-RARE is that it has an AGGTCA-like motif in common with an estrogen-responsive element (ERE). The composite RARE/ERE contributes to the functional interaction between retinoid receptors and the estrogen receptor (ER) and their ligands. In CV-1 cells, cotransfection of the retinoid and estrogen receptors led to mutual inhibition of the other's activity, while an RA-dependent inhibition of ER activity was observed in breast cancer cells. Furthermore, the lactoferrin-RARE/ERE showed differential transactivation activity in different cell types. RAs could activate the lactoferrin-RARE/ERE in human leukemia HL-60 cells and U937 cells but not in human breast cancer cells. By gel retardation analyses, we demonstrated that strong binding of the endogenous COUP-TF in breast cancer cells to the composite element contributed to diminished RA response in these cells. Thus, the lactoferrin-RARE/ERE functions as a signaling switch module that mediates multihormonal responsiveness in the regulation of lactoferrin gene expression.
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PMID:A retinoic acid response element that overlaps an estrogen response element mediates multihormonal sensitivity in transcriptional activation of the lactoferrin gene. 762 14

A number of studies have demonstrated the ability of retinoic acid (RA) to inhibit the growth of estrogen receptor-positive (ER+) human breast cancer cell lines. The precise mechanism of growth inhibition is not known. However, the biological effects of RA in other model systems have been shown to be mediated via the nuclear retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). While several laboratories have examined the expression of RARs in various breast cancer cell lines, no information is available concerning the role of the RXRs and 9-cis-RA, the natural ligand of RXRs, in the response of breast cancer cells to RA. Using a representative panel of breast cancer cell lines, we determined the effect of 9-cis-RA on growth and cell cycle stage distribution, analyzed steady-state mRNA levels of RXR-alpha, -beta, and -gamma, and determined the effect of all-trans-RA and 9-cis-RA on RXR expression. Our results show that: (1) the growth of ER+/RA-sensitive breast cancer cells is inhibited by treatment with 9-cis-RA by blocking entry into S phase; (2) both ER+/RA-sensitive and ER-/RA-resistant breast cancer cell lines express RXR-alpha and RXR-beta mRNAs but not RXR-gamma; however, levels of these transcripts did not correlate with the RA response; and (3) levels of RXR-alpha and RXR-beta mRNA were not significantly altered following treatment with either all-trans-RA or 9-cis-RA. These results suggest that the mechanism responsible for the retinoid sensitivity of breast cancer cells does not involve transcriptional modulation of the RXRs by RA.
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PMID:Effect of 9-cis-retinoic acid on growth and RXR expression in human breast cancer cells. 764 8

The ability of retinoids to modulate the proliferation as well as the morphological and functional differentiation of normal mammary epithelial cells isolated from pubescent female virgin rats was evaluated in serum-free primary culture. The retinobenzoic acid derivative RE80, present continuously or for only a limited time in culture, inhibited proliferation with an IC50 of less than 10(-10) M. In contrast, all-trans-retinoic acid (RA) inhibited proliferation with an IC50 of approximately 10(-8) M. In addition to effects on proliferation, RE80 and RA stimulated end bud colonies to differentiate to lobular alveolar colonies, inhibited alveolar budding, and suppressed the outgrowth of squamous colonies. Both retinoids also markedly stimulated functional differentiation, as assessed by accumulation of the major milk protein casein, and stimulated the synthesis of a approximately 73- to 74-kilodalton protein identified as a member of the transferrin family. Moreover, both retinoids stimulated cell death in the differentiated cell population. RE80 was approximately 100-fold more potent than RA for all of these effects. These data suggest that several mechanisms may contribute to the chemopreventive and/or therapeutic efficacy of retinoids in breast cancer, including inhibition of proliferation, stimulation of cell death, and/or induction of differentiation.
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PMID:Modulation of normal mammary epithelial cell proliferation, morphogenesis, and functional differentiation by retinoids: a comparison of the retinobenzoic acid derivative RE80 with retinoic acid. 789 82

Interleukin (IL) 1 alpha induced the up-regulation of cell-surfac-expressed epidermal growth factor (EGF) receptor on both MDA-MB-468 and BT-20 breast cancer cell lines. IL-1 beta and tumor necrosis factor alpha (TNF-alpha) increased the EGF receptor surface expression only on BT-20 breast carcinoma cells. 12-O-tetradecanoylphorbol 13-acetate (TPA) induced up-regulation of EGF receptor on MDA-MB-468 cells, and a marginal but significant increase was determined in BT-20 cells and in interferon gamma (IFN-gamma)-treated MDA-MB-468 cells. CD15 (Lewisx) antigen was down-regulated on MDA-MB-468 cells by TNF-alpha, TPA, IL-1 alpha, as well as by IFN-gamma and all-trans-retinoic acid. 1,25(OH)2-vitamin D3 up-regulated the CD15 antigen surface expression on MDA-MB-468 cells.
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PMID:Modulation of EGF receptor and CD15 (Lewisx) antigen on the cell surface of breast carcinoma cell lines induced by cytokines, retinoic acid, 12-O-tetradecanoylphorbol 13-acetate and 1,25(OH)2-vitamin D3. 790 17


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