A novel binding site for a synthetic progestagen in breast cancer cells

Colletta, Anthony A.; Howell, Fiona V.; Baum, Michael

doi:10.1016/0022-4731(89)90409-3

Cited by 17 publications

(10 citation statements)

References 15 publications

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“…Growth inhibition by Gestodene does not involve the classical progesterone receptor, but appears to be mediated by a novel high affinity intracellular binding site that has recently been identified uniquely in breast cancer cells and tissues (5,6). Thus the degree of inhibition by Gestodene correlated well with levels of GBS.…”

Section: Discussionmentioning

confidence: 94%

“…The cells used in this study, together with their maintenance media, are as follows: MCF-7, breast cancer cells, maintained in MEM with 10% FCS, 0.2 iu bovine insulin per ml, 1 mM sodium pyruvate, 2 mM L-glutamine, and nonessential amino acids (NEAA) (all media and additives were obtained from Gibco Laboratories Ltd., UK); T47D, breast cancer cells, maintained in RPMI 1640 medium with 10% FCS, 0.2 iu bovine insulin per ml, and 2 mM L-glutamine; (6). To assess the effect ofGestodene, compared with a range ofcontrol compounds on the growth of breast cancer cells, dose-response relationships in monolayer culture were undertaken.…”

Section: Methodsmentioning

confidence: 99%

“…Before these experiments the cells were maintained for 3 wk in phenol red-free media (7) phenol red-free medium containing 5% DCC-FCS together with the additives listed above and allowed to attach for 24 h. After this time the seeding medium and any dead cells were removed and replaced with 5 ml of fresh medium. These were then made in quadruplicate, 10, 100, 1000, and 10,000 nM, with respect to the following drugs: dexamethasone, 17,21 -dimethyl-19-nor-4,9-pregnadiene-3,20-dione (R5020); 17-alpha-ethinyl-13-beta-ethyl-17-beta-hydroxy-4, 1 5-oestradiene-3-one (Gestodene); 17-alpha-hydroxy-6-methyl-4-pregnane-3,20-dione-17-acetate (MPA); 1 3-ethyl-11-methylene-18,19-dinorpregn-4-en-20-yn-17-ol-3-one (3-keto-desorgestrel); tamoxifen, 4-chloro-1,2-diphenyl-1-[4-(2-(N,N-dimethylamino)ethoxy)phenyl]-l-butene (toremifene) (6).…”

Section: Methodsmentioning

confidence: 99%

“…The binding site for this steroidal compound, Gestodene, appears to be expressed uniquely in malignant breast tumor biopsies and cell lines, and not in normal tissues or other malignancies (5,6). Preliminary studies indicating that Gestodene is growth inhibitory for malignant breast cell lines led us to investigate the possibility that this agent might be acting via the induction of TGF-beta.…”

Section: Introductionmentioning

confidence: 99%

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The growth inhibition of human breast cancer cells by a novel synthetic progestin involves the induction of transforming growth factor beta.

et al. 1991

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Recent experimental work has identified a novel intracellular binding site for the synthetic progestin, Gestodene, that appears to be uniquely expressed in human breast cancer cells. Gestodene is shown here to inhibit the growth of human breast cancer cells in a dose-dependent fashion, but has no effect on endocrine-responsive human endometrial cancer cells. Gestodene induced a 90-fold increase in the secretion of transforming growth factor-beta (TGF-beta) by T47D human breast cancer cells. Other synthetic progestins had no effect, indicating that this induction is mediated by the novel Gestodene binding site and not by the conventional progesterone receptor. Furthermore, in four breast cancer cell lines, the extent of induction of TGF-beta correlated with intracellular levels of Gestodene binding site. No induction of TGF-beta was observed with the endometrial cancer line, HECI-B, which lacks the Gestodene binding site, but which expresses high levels of progesterone receptor. The inhibition of growth of T47D cells by Gestodene is partly reversible by a polyclonal antiserum to TGF-beta. These data indicate that the growth-inhibitory action of Gestodene may be mediated in part by an autocrine induction ofTGFbeta. (J. Clin.

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Section: Discussionmentioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The growth inhibition of human breast cancer cells by a novel synthetic progestin involves the induction of transforming growth factor beta.

et al. 1991

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“…The effect of gestodene on TGF-,3 has not been reported. To further our understanding of hormonal regulation of TGF-,B expression in breast cancer cells, we studied the effect of gestodene on T47-D cells, which, like other breast cancer cells, have been shown to contain an as yet uncharacterized gestodene-specific binding site (10). In contrast to the effect of estradiol on TGF-,B3 expression by T47-D cells, the relative abundance of the two TGF-j3 transcripts was shifted by treatment of cells with gestodene (Fig.…”

Section: Resultsmentioning

confidence: 99%

Enhanced translational efficiency of a novel transforming growth factor beta 3 mRNA in human breast cancer cells.

1994

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The mRNA for transforming growth factor P3 (TGF-133) includes a long (1.1-kb) 5' noncoding region which exerts a potent inhibitory effect on translational efficiency. We now report that many human breast cancer cell lines (T47-D, SK-BR-3, ZR-75-1, and BT-474) express two mRNA species for TGF-03: the 3.5-kb transcript previously described as the only TGF-P3 mRNA species in cells and a novel 2.6-kb transcript which lacks -870 nucleotides from the 5' noncoding region. The 5' end of the shorter transcript was sequenced, establishing it to be a 5' truncation of the full-length TGF-133 transcript. Estradiol decreased mRNA levels of both TGF-13 mRNA transcripts to an equivalent degree in estrogen receptor-positive cells. In contrast, the synthetic progestin gestodene altered the relative abundance of the two transcripts, preferentially diminishing the expression of the 2.6-kb transcript. The potential for enhanced mRNA translation attributable to the shorter 5' noncoding region was evaluated by transfection of cells with chimeric plasmid constructs in which the transcription unit consisted of coding sequence for chloramphenicol acetyltransferase downstream of the 5' noncoding sequence from TGF-13. The translational efficiency of chloramphenicol acetyltransferase-encoding mRNA containing the shorter 5' noncoding region of the 2.6-kb TGF-133 transcript was approximately seven times greater than with the full-length 5' noncoding region of TGF-03. Polysome analysis of TGF-133 mRNA in SK-BR-3 cells supported the hypothesis that the 2.6-kb transcript was more actively engaged in translation.The term transforming growth factor v (TGF-P) has come to represent a family of structurally related proteins with a wide range of biological activities. Although TGF-P was initially identified as a stimulator of the anchorage-independent growth of some fibroblast cell lines, it has become evident that it is a potent inhibitor of cell proliferation for many other cell types, including epithelial, endothelial, and hematopoietic cells. In addition, TGF-j is believed to play an important role in such diverse processes as wound repair, development, tumorigenesis, and immunosuppression. Since the discovery of the first member of this gene family a decade ago, several isoforms of TGF-,B with similar biological activities have been characterized. In mammals, three isoforms of TGF-P have been identified, each encoded by a distinct gene (44 that all three TGF-,s are expressed in calf and adult bovine mammary glands. The highest levels of expression were seen with probes specific for TGF-33 mRNA (36). TGF-13 mRNA expression has been reported for a variety of human and murine tissues and cell lines. In all reports, a single -3.5-kb mRNA species has been detected (5, 6, 13-15, 40, 41, 45, 51, 54, 56). We and others have determined that the 5' noncoding region of TGF-P3 mRNA is 1.1 kb in length and contains 11 open reading frames (2, 33). Consistent with the scanning model for initiation of mRNA translation (30), we have observed marked inhibition of...

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The role of TGF‐β production in growth inhibition of breast‐tumor cells by progestins

Kalkhoven

Kwakkenbos-Isbrücker

Mummery

et al. 1995

Intl Journal of Cancer

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We have studied the influence of synthetic progestins on the estrogen-induced proliferation and type-beta transforming-growth-factor (TGF-beta) production of 3 breast-tumor cell lines. In long-term growth experiments, progestins inhibited proliferation of T47D cells, while a specific T47D variant and MCF7 cells were not affected, despite the presence of functional progesterone receptors. The effect of progestins was biphasic, since an initial stimulation of proliferation was followed by a prolonged inhibition. This response suggests the involvement of a progestin-induced negative growth regulator. We show here that TGF-beta s do not fulfill this role since (i) the progestin-induced T47D cells are not sensitive to TGF-beta 1, -beta 2 or -beta 3, (ii) secretion of TGF-beta s is decreased by progestins in all 3 cell lines, and (iii) TGF-beta neutralizing antibodies do not reverse progestin-induced growth inhibition. Furthermore, evidence was obtained that medium conditioned by T47D cells does not contain any other growth inhibitor to which this cell line responds in a negative autocrine manner. In contrast, MCF7 cells are growth-inhibited by all 3 TGF-beta isoforms, but are not growth-inhibited by progestins, suggesting that there is no correlation between growth inhibition by progestins and responsiveness to and production of TGF-beta in vitro. Although TGF-beta is a strong growth inhibitor of normal mammary tissue, recent evidence suggests that, in malignant tissue, enhanced TGF-beta secretion correlates with increased malignancy. Therefore, a progestin-induced decrease in TGF-beta production, as observed here, may lead to enhanced proliferation of normal but not malignant mammary epithelium.

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A novel binding site for a synthetic progestagen in breast cancer cells

Cited by 17 publications

References 15 publications

The growth inhibition of human breast cancer cells by a novel synthetic progestin involves the induction of transforming growth factor beta.

The growth inhibition of human breast cancer cells by a novel synthetic progestin involves the induction of transforming growth factor beta.

Enhanced translational efficiency of a novel transforming growth factor beta 3 mRNA in human breast cancer cells.

The role of TGF‐β production in growth inhibition of breast‐tumor cells by progestins

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