Milea Timbergen

42 Various studies investigated the effect of TFG-ß and epidermal growth factor (EGF) on DTF cell lines and stimulation with these cytokines caused up- and down regulation of various target genes (e.g., SMAD4), changes in β-catenin levels, and increased production of glycosaminoglycan and collagen. Additionally, treatment with EGF increased DTF cell motility (Table 1) 65-68 . Cross-talk between the insulin-like growth factor (IGF) and the oestrogen receptor (ER) mediated signalling has been demonstrated in breast-cancer cells. Activation of MAPK, which is located downstream of IGF-1, enhances ER induced transcription via ER phosphorylation. Therefore, it is presumed that growth factor signalling pathways and the oestrogen pathways complement and overlap each other (reviewed by Dhingra et al. 139 ). Toremifene, a drug which also inhibits collagen synthesis and protein kinase C, works on both the growth factor regulatory signalling pathway and the oestrogen pathway and will be discussed in the next section. The role of the oestrogen driven pathway in desmoid-type fibromatosis The oestrogen driven pathway Oestrogens affect various physiological processes that concern the development of the reproductive system and several reproductive functions. The role of oestrogens in cancer has been described in breast cancer and uterine tumours (reviewed by Dhingra et al. 139 ). Two subtypes of oestrogen receptors (ER) haven been identified: ER-ɑ (ESR1) and ER-ß (ESR2) to which oestrogens can bind. Without the ligand, the intracellular ER is considered to be in an inactive state, forming a complex with two heat shock proteins (Hsp90 and Hsp56) and various other proteins. Upon binding of the ligand oestrogen, Hsp90 is detached from the complex which leads to ER phosphorylation. Next, the ER dimerises and translocates to the nucleus where it can interact with specific DNA sequences, oestrogen response elements (ERE), causing transcriptional activation (reviewed by Dhingra et al. 139 . and Picariello et al. 140 ). The oestrogen driven pathway and its role and therapeutic potential in des- moid-type fibromatosis The role of sex hormones, particularly oestrogen, in DTF tumorigenesis is primarily based on clinical observations, and prompted the use of anti-hormonal agents. DTF arises frequently in females at the reproductive age 4 . Moreover, tumour growth during pregnancy, 2