In Vitro Effects of MLT on Breast Cancer

In addition to animal models, the effects of MLT on breast cancer have been investigated through in vitro studies using several different human breast tumor cell lines. Examination of MLT's effects on various breast cancer cell lines shows that MLT suppresses the growth of cells which express the estrogen receptor (ER-positive cell lines), but has no effect on ER-negative cell lines (13). One of the most extensively studied cell lines is the ER-positive MCF-7 human breast cancer cell line derived from the pleural effusion of a woman with metastatic adenocarcinoma of the breast (14). This breast cancer cell line expresses the ER and the estrogen-inducible progesterone receptor (PgR), as well as other steroid receptors, such as the androgen (AR) and glucocorticoid (GR) receptors (15,16). Studies investigating the effects of MLT on MCF-7 cells have shown that 10-9M MLT induces a 60%-80% inhibition of cell proliferation after 7 days of treatment (10). The effective growth-inhibitory concentration of MLT ranges from 10-9M to 10-11M, which corresponds to peak physiological night and daytime values, respectively (17). The antiproliferative effects of MLT appear to be limited to a very narrow range; both sub-physiological and supra-physiological concentrations of MLT are ineffective in suppressing MCF-7 cell proliferation (8).

Since MLT has been shown to exert antiproliferative effects only on ER-positive cell lines, it is possible that MLT's effects are mediated through modulation of the estrogen response pathway. Molis et al. (18) reported that 10-9 M MLT, a concentration previously shown to inhibit MCF-7 cell proliferation, is also able to significantly repress ER mRNA expression and ER protein levels as early as 6 h after treatment. It has also been shown that MLT does not compete with labeled estrogen for binding to the ER, demonstrating that MLT's inhibitory effects on cell proliferation do not result from interference with estrogen binding (19).

The antiproliferative effects of MLT have also been shown to be serum-dependent, suggesting that interaction between MLT and specific serum components may be necessary in order to produce its growth-inhibitory effects (10). Two hormones, estrogen and prolactin, both of which exert a mitogenic effect on MCF-7 cells, are present in the serum, and MCF-7 cells express receptors for both hormones. It is possible that MLT may exert its antiproliferative effects by interfering with estrogen and/or pro-lactin-stimulated growth. In support of this hypothesis, Blask and Hill (10) reported that MLT inhibits estrogen-stimulated growth in MCF-7 cells, and that the loss of MLT's growth-inhibitory effects seen in serum-free, defined media can be partially reconstituted by the addition of exogenous prolactin. These findings suggest that the growth-inhibitory effects of MLT may involve important interactions between MLT and other hormones and growth factors present in serum.

Studies using flow cytometry show that MLT inhibits MCF-7 cell proliferation by delaying the G1 to S transition in the cell cycle, indicating that the antiproliferative effects of MLT may be cell cycle-specific (20,21). Cos et al. (22) have further shown that MLT significantly increases the duration of the cell cycle of MCF-7 cells from 20.36 h to 23.48 h. These data support the belief that MLT exerts its antiproliferative effects, at least in part, through a cell cycle-specific mechanism that delays the entry of MCF-7 cells into mitosis. Cos et al. (23) have also shown that MLT inhibits DNA synthesis in MCF-7 cells, which suggests that the antiproliferative effects of MLT on breast cancer cells may also depend on its inhibitory actions on DNA synthesis.

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