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Background: 1,25-dihydroxycholecalciferol has been previously reported to negatively regulate human breast cancer cell growth., Material and Methods: The antiproliferative effect of 1,25-dihydroxycholecalciferol (Ro 21-5535) and of the two non hypercalcemic analogs (1a,25-dihydroxy-16-ene-23-yne-26,27-hexafluorocholecalciferol+ ++, Ro 24-5531 and 1a,25-dihydroxy-16-ene-23-yne-26,27-hexafluoro-19-nor-cholec alciferol, Ro 25-6760) was studied in MCF-7 and MDAMB-468 human breast cancer cell lines. Cell cycle distribution and apoptosis were evaluated by flow cytometry. Steroid receptor modulation was investigated by radioligand assay., Results: The most effective drug was the Ro 25-6760 which at concentrations ranging between 1-100 nM caused a dose dependent growth inhibition apparently due to accumulation in G0/G1. Vitamin D3 analogs (10 nM) significantly counteracted the growth stimulation induced by TGF-a and IGF-I as well as the paracrine stimulation observed in co-cultures. They antagonized estradiol-promoted growth stimulation and progestrone receptor induction in MCF-7 cells., Conclusion: Vitamin D3 analogs represent a class of clinically attractive drugs for treatment of breast cancer due to their ability to counteract estradiol and growth factor-induced growth stimulation.

Background: Reports about the effects of progestins on cell proliferation are contradictory. We investigated the effect of progesterone, medroxyprogesterone acetate, megestrol acetate, ORG 2058 and the antiprogestin RU 486 on two hormone-dependent cell lines, T47D and MCF-7 (characterized by a different content of PgR). The aim of the study was to understand the eventual ability of progestins to interfere with cell proliferation stimulated by estradiol and various growth factors (TGF-a, IGF-I, IGF-II)., Material and Methods: MCF-7 and T47D cells were maintained in DMEM/F12 medium supplemented with 2% FCS while experiments were carried out in the same culture medium using DCC-stripped FCS., Results: In the absence of estradiol, all tested progestins generally tended to stimulate cell growth in the T47D cell line, but in the MCF-7 cell line only the highest concentrations (10(-6) M and 10(-7) M) were found to be stimulatory. In contrast, in the presence of 10(-8) M estradiol, progestins tended to inhibit cell growth stimulation in MCF-7 and T47D cell lines. The antiprogestin RU 486 exerted a stimulatory effect similar to that promoted by estradiol itself in MCF-7 cells. Instead, in T47D cells, RU 486 did not modify cell growth in the absence of estradiol, but tended to counteract the estradiol-promoted cell proliferation. In MCF-7 cells, medroxyprogesterone acetate and megestrol acetate were also able to effectively counteract the cell growth induced by TGF-alpha. However, none of these progestins was able to abolish cell proliferation promoted by IGF-I or IGF-II., Conclusion: We therefore concluded that failure to respond to progestin treatment may be due to the very heterogeneous nature of human breast tumors and to the inability of these molecules to interfere with the IGF-R pathway.

The effect of some new antiestrogens (ICI 164384, ICI 182780, Ly 133314 and Ly 117018) on the growth of a panel of breast cancer cell lines (MDA-MB 231, BT20, MCF7 and T47D) was studied. Their antiestrogenic activity was investigated in the presence of a physiologic concentration of estradiol and compared with the effect displayed by tamoxifen in the same experimental conditions. Tamoxifen confirmed its antagonistic activity in the presence of estradiol, whereas when given alone it did not exhibit a clear antiproliferative effect. All other compounds showed variable activity: ICI 164384 and ICI 182780 exerted a variable inhibitory effect in all cell lines, but only in the absence of estradiol; Ly 133314 and Ly 117018 did not show a clear antagonistic activity and sometimes had a synergistic effect with estradiol in increasing cell growth. These results indicate an extreme variability in terms of antagonistic effect of these new compounds and suggest their inadequacy to replace tamoxifen as an antiestrogen during endocrine treatment. Interestingly, ICI 164384 exerted an antiproliferative action also an estrogen receptor-negative cell lines, probably through an alternative mechanism non estrogen receptor-mediated, supporting the hypothesis that it could be effective on estrogen receptor-positive as well as estrogen receptor-negative tumors.

The effects of toremifene, an antiestrogen, and its two main metabolites (4-hydroxy- and N-desmethyltoremifene) on cell proliferation have been tested in a series of breast cancer cell lines, with positive (MCF7, ZR 75.1, T47D, 734B) or negative steroid receptor status (MDA-MB 231, BT20). Drug effects were evaluated at concentrations similar to those obtained in breast cancer patients on toremifene treatment, and in the presence or absence of estradiol. Results showed that, for both positive and negative cell lines, high concentrations of the antiestrogens (10(-6)M) were inhibitory, while lower doses (10(-7)M, 10(-8)M) were stimulatory. These data confirm the biphasic behaviour of toremifene and its derivatives. In terms of a clinical application of toremifene, these results seem to suggest that while high doses of toremifene and its derivatives might be therapeutic, lower concentrations might stimulate cell growth and enhance tumor progression.

Laboratory data from Milan and Houston were evaluated to determine the extent to which the distribution of estrogen receptor (ER) and progesterone receptor (PgR) has changed with time. Results from over 11,500 ER and over 8,200 PgR determinations (6,194 ER and 3,127 PgR from Milan) were analyzed. All assays in Milan were performed by a dextran-coated charcoal method and in Houston by a sucrose density-gradient method. The data demonstrate a time-dependent, upward drift in the amount of ER and PgR detected, with the effect most pronounced at the lower end of the distribution curves. We attribute this change to optimization of all facets of the receptor assay procedures (tissue harvesting and storage) as well as to a change in breast cancer biology. These results suggest that studies correlating certain biological parameters with receptor status (whether using qualitative or quantitative scales) need to be re-examined. For example, a population of 349 node-negative patients who did not receive any adjuvant treatment was studied in Milan to determine any association between disease-free survival (DFS) and receptor status. If the "historical" threshold values (10 fmol/mg protein) were used to determine receptor status, no significant difference in DFS at 5 years was detected. Even the combination of ER and PgR did not improve the predictive power of receptor status. In the premenopausal subgroup, ER status did predict the 5-year DFS. However, if the threshold value for PgR was adjusted to 25 fmol/mg protein, patients with ER-positive, PgR-positive tumors had significantly better 5-year DFS than patients with ER-negative, PgR-negative tumors. In addition, PgR status alone was associated with significantly improved 3-year DFS if the subgroups of PgR less than 5 fmol/mg protein and PgR greater than 100 fmol/mg protein were compared. We conclude from these data that: 1) historical threshold values for receptor positivity should be re-examined in all laboratories; 2) studies involving receptor results determined over an extended period of time should attempt to "normalize" these results; and 3) the quantitative assessment of receptor status should be used whenever possible.

Steroid receptors were measured in a series of 30 operable canine mammary gland tumors; both cytoplasmic estrogen (ERc) and progesterone (PgRc) receptor mean concentrations were very low with respect to the mean levels found in humans. Therefore a study was designed to modulate receptor levels by administration of Tamoxifen and Etretinate, either alone or in combination. Forty dogs with resectable, histologically documented mammary gland tumors were subdivided into the following treatment groups: a. Etretinate (1 mg/kg/d) p.o. for 7 days followed by Tamoxifen (0.7 mg/kg/d) p.o. for 7 days; b. Tamoxifen (0.7 mg/kg/d) p.o. for 14 days; c. Etretinate (1 mg/kg/d) p.o. for 14 days; d. 14 days placebo, and cytoplasmic ERc and PgRc and nuclear ER (ERn) were measured before and after the treatment. An increase of ERc and ERn was observed after administration of Tamoxifen, while an increase of ERc only was seen after treatment with Etretinate. We conclude that canine mammary tumors are indeed hormone sensitive despite their very low receptor concentrations and a suitable treatment can in fact modulate receptor levels. However, further studies are needed better to define the optimal treatment regimen in order to achieve maximal steroid receptor induction.