Retinoids and Breast Cancer

Studies using human breast cancer cell lines show that retinoids inhibit the growth of ER-positive but not ER-negative cell lines (54,55). This may be due to the fact that ER-positive breast cancer cells express higher levels of RAR than ER-negative breast cancer cells. For example, ER-positive MCF-7 breast cancer cells are RARa and P-pos-itive and respond to the growth-inhibitory effects of RA; while ER-negative MDA-MB-231 breast cancer cells are RARa and P -negative and are unresponsive to the anti-mitogenic actions of RA. Several growth-regulatory pathways are affected when breast tumor cell lines are exposed to RA (56). For example, in MCF-7 cells, RA increases the activity of insulin-like growth factor binding protein one (IGF-BP-1), thereby reducing the mitogenic efficacy of IGF-1 (57). In addition, treatment of ERpositive MCF-7 and T47D human breast cancer cells with RA induces secretion of growth-related proteins, including TGF-P (59, and suppresses the expression of several key growth-regulatory proteins, including the ER, progesterone receptor (PgR) and TGF-a (58,59). Differentiation and loss of Her-2/neu expression may also be induced by RA (60).

Both natural and synthetic retinoids have been used in large doses in vivo to prevent DMBA- or NMU-induced rat mammary carcinogenesis (61,62). Retinoid treatment delays the appearance of mammary tumors and decreases the incidence and multiplicity of tumors. In addition, studies have shown that, under certain conditions, these carcinogen-induced tumors can be induced to regress. Castration of rats prior to administration of NMU prevents tumor formation but does not routinely induce the regression of established tumors (63). However, Lacroix et al. (62) found that atRA in combination with ovariectomy can effectively inhibit the growth of established NMU-induced mammary tumors. The majority of studies have examined the effects of atRA and 13-cis -RA, both of which have been shown to have moderate efficacy in the prevention of tumors in the NMU-mammary tumor model (64). More recently, 9cRA has been shown to have greater efficacy than atRA in the prevention of both the incidence and multiplicity of rat mammary carcinoma (65). A report by Anzano et al. (66) demonstrated that 9cRA, in combination with tamoxifen is more effective that 9cRA alone in preventing mammary tumor formation. Retinoids have also been found to be effective chemotherapeutic agents in human cancer clinical trials (67).

Although highly efficacious in the treatment of breast cancer, the clinical use of retinoids is severely limited by its toxicity (67). To circumvent retinoid-induced toxic-ity, pharaceutical companies have begun to develop ligand-specific synthetic retinoids. However, this approach has met with only limited success. Recent reports from Got-tardis et al. (68) and Bischoff et al. (69) found that an RXR-selective ligand, LGD1069 (Targretin), is very effective in preventing the development and inducing the regression of rat mammary tumors. Other synthetic ligands have not been found to be as useful. Since the growth of endocrine-responsive breast tumors depends heavily on the hormonal milieu presented to the tumor cells and the cross-talk between various signaling pathways activated by the different hormones and growth factors, it seems likely that other hormones or growth factors, when used in combination with RA, might lead to increased efficacy without the risk of toxicity. For example, we have found that a sequential treatment regimen of MLT for 24 h followed by atRA results in the decreased expression of the ER and a significant induction of TGF-P, and that the combination of MLT and atRA induces apoptosis (programmed cell death) of hormone-responsive breast tumor cells. We have also demonstrated that the in vivo combination of MLT and 9cRA is more efficacious in the prevention of NMU-induced rat mammary tumors that either MLT or 9cRA alone.

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