Hypothetical Correlation Of Proliferation Of The Breast Cancer Cell And Sult Activity

Maximal epithelial mitosis of the normal breast cell is found between 22 and 26 days of the cycle, which corresponds to the high levels of estradiol and progesterone (Longacre and Bartow, 1986). During pregnancy, it is suggested that the elevated values of circulating progesterone are responsible for the induction of lobular-alve-olar development, to prepare the breast for lactation (Russo and Russo, 2002; Topper and Freeman, 1980). The data on the effect of progesterone on breast epithelial proliferation are contradictory. It has been found that progesterone can increase DNA synthesis in normal breast epithelium in organ culture (Laidlaw et al., 1995).

Using normal human breast epithelial cells, it was demonstrated that the progestin promegestone can decrease cell proliferation (Gompel et al., 1986; Malet et al., 2000). These authors also found that progestins can inhibit the proliferative effect

FIGURE 8.6 Effects of the progestin R-5020 (promegestone) on the SULT activity and the mRNA expression of SULT1A3 in the hormone-dependent T-47D human breast cancer cell line. Relative expression of the mRNA (using RT-PCR amplification) and the estrogen sulfation activity (in pmol/mg protein/h) in T-47D cells nontreated (control) and treated with R-5020 at the concentration of 5 x 10 or 5 x 1 0-7mol/L. The control value is assigned 100%. The data represent the mean ± S.E.M. of two to three experiments. Quoted from Chetrite G, Le Nestour E, Pasqualini JR, J Steroid Biochem Molec Biol 66: 295-302, 1998. With permission.

FIGURE 8.6 Effects of the progestin R-5020 (promegestone) on the SULT activity and the mRNA expression of SULT1A3 in the hormone-dependent T-47D human breast cancer cell line. Relative expression of the mRNA (using RT-PCR amplification) and the estrogen sulfation activity (in pmol/mg protein/h) in T-47D cells nontreated (control) and treated with R-5020 at the concentration of 5 x 10 or 5 x 1 0-7mol/L. The control value is assigned 100%. The data represent the mean ± S.E.M. of two to three experiments. Quoted from Chetrite G, Le Nestour E, Pasqualini JR, J Steroid Biochem Molec Biol 66: 295-302, 1998. With permission.

provoked by estradiol; however, McManus and Welsch (1984) and Longman and Buehring (1987) demonstrate no effect.

The proliferative effect of progestins using various isolated breast cancer models — cell lines, organ culture, or transplantation of breast cancer cells — in nude mice is contradictory as it was reported that these compounds can either inhibit (Botella et al., 1994; Horwitz and Freidenberg, 1985; Musgrove et al., 1991; Vignon et al., 1983), stimulate (Catherino and Jordan, 1995; Jeng et al., 1992; Kalkhoven et al., 1994), or have no effect (Schatz et al., 1985).

The biological action of progestins is derived from many factors: structure, affinity for the progesterone receptor or for other steroid receptors, the experimental conditions (source of the cell lines, media, sera, presence of phenol red, insulin, duration of treatment), the dose concentrations, and their metabolic transformation (Braunsberg et al., 1987; Schoonen et al., 1995a, 1995b; van der Burg et al., 1992).

Interesting information was obtained with nomegestrol acetate (Lutenyl®), a 19-nor-progestin derivative. This compound does not possess estrogenic activity and is exclusively antiproliferative in MCF-7 and T-47D breast cancer cells. Recently, it was demonstrated also that another progestin, medrogestone, can inhibit proliferation of the T-47D cells as well as block the proliferative effect provoked by estradiol (Pasqualini and Chetrite, 2002). Since estradiol plays an important role in regulating the proliferation of breast cancer cells via the induction or suppression of growth factors, the control of the hormone by SULT1E1 activity could be an important aspect in the mechanism of cell growth and proliferation.

As was indicated in preceding sections, SULT1E1 is present mainly in the normal breast cell and is active at nanomolar concentrations of E2; consequently, it can block cell proliferation by formation of the inactive E2S. However, in the breast cancer cells, SULT1A1 is present and is active only at micromolar concentrations; most of the E2 remains in an unconjugated form and can be involved in cell proliferation. As the progestin medrogestone can stimulate SULT1E1 in breast cancer cells and as this compound can block the proliferation of T-47D cells (Figure 8.7), it is suggested that the antiproliferative action of medrogestone is correlated with the stimulatory effect of SULT1E1 in this breast cancer cell. This hypothetical mechanism of the correlation of SULT1E1 and proliferation in breast cancer is schematically represented in Figure 8.8 (A, B, and C).

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