ABSTRACT
The research to date suggests that sex steroids may modulate VEGF production in normal and tumor breast tissue, although it is not yet clear whether this is an effect of estradiol alone or whether progesterone is also involved (Dabrosin et al. 2003; Hyder 2006). Addition of progesterone to estradiol in tissue culture experiments with normal breast biopsies did not alter the estrogen-induced VEGF levels (Dabrosin et al. 2003). Importantly, it has not been proven whether VEGF in the normal breast can be associated with the initiation or progression of tumors. The effects of progesterone on angiogenesis and VEGF expression in breast cancer are poorly understood. Consequently, there is little information relating to the possible role of progesterone in angiogenesis and/or the regulation of VEGF expression. Several reports demonstrated that both natural and synthetic progestins induced VEGF in breast cancer cells (Hyder and Stancel 2002; Liang and Hyder 2005; Mirkin et al. 2005). The human VEGF promoter was found to have progesterone response elements, which seems to be cell specific for modulating VEGF synthesis (Mueller et al. 2003; Wu et al. 2005). In breast cancer cells, the region that seems to induce VEGF expression requires a Sp-1 region since a mutation in this region eliminates the ability of progestin to induce the VEGF promoter (Wu et al. 2005). It is possible that Sp-1 and the progesterone receptor might work together to produce a response, which was reported for estrogen-dependent VEGF expression in breast cancer cells (Stoner et al. 2004). There is evidence that progesterone receptor isoforms may be important factors for the induction of VEGF in breast cancer cells. Progesterone receptor-B is a more potent inducer of VEGF than progesterone receptor-A (Wu et al. 2004), which suggests that progesterone receptor-Brich tumors will be faster growing and more vascularized than tumors containing predominantly progesterone receptor-A. The study by Sortorius et al (Sartorius et al. 2003) provides additional support for this idea; this study reported that larger tumors could be produced when progesterone receptor-B-containing cells were grown in. Furthermore, both anti-estrogens and anti-progestins appear to induce VEGFs by breast cancer cells are rich in progesterone receptor-B, implying that anti-hormones are seen differently depending on which progesterone receptor isoform is present (Wu et al. 2004; Wu et al. 2005). All synthetic progesterones investigated were able to induce VEGF in breast cancer cells in a mechanism that involves both PI3K and MAPK pathways (Hyder and Stancel 2002; Liang and Hyder 2005). Interestingly, Wu et al reported that the regulation of the VEGF gene occurred in a either a cell or ligand-dependent manner (Wu et al. 2005). Treatment with PI3K inhibitors attenuated both the cellular expression of VEGF and secretion of VEGF protein. Treatment with MAP kinase inhibitors, on the other hand, did not inhibit gene transcription in certain cells, but did attenuate protein secretion; in this case suggesting that progesterone can regulate VEGF expression at both at the levels of transcription and posttranscription. Interestingly, progesterone-dependent VEGF expression could
be blocked at both the protein and transcriptional level, by anti-estrogen therapy using ICI 182,780, supporting the idea that there may be crosstalk mechanisms involved in regulating these two receptors (Hyder and Stancel 2002). The picture emerging is that with breast cancer cells, the regulation of angiogenic pathway involving VEGF and VEGF receptors is under the control of both estrogens and progestins. Still, very little has been established detailing the molecular mechanism(s) involved in regulating this expression, or the cellular consequences resulting from inducting or suppressing VEGF and VEGF receptors in breast tissues.
