Increased promoter methylation can not account decreased NESG1 expression in NPC, thus a different mechanism is likely responsible for its loss. The secreted Slit glycoprotein and its Robo receptor were originally identified as important axon guidance molecules in the developing Drosophila nervous system. Their role is evolutionary conserved as vertebrate SLIT and ROBO also inhibit aberrant neuron migration. However most members of the vertebrate SLIT and ROBO families are also expressed outside of the nervous system and have been linked with the development of a variety of organs including the mammary gland and ovary. During organogenesis the SLIT/ROBO interaction is thought to regulate numerous processes including cell proliferation, apoptosis, adhesion and LDN-193189 migration of non-neuronal cells. Molecules that have important roles in development are often dysregulated in cancer. Indeed the SLITs and ROBOs are candidate tumour suppressor genes whose expression is reduced in numerous epithelial tumour cell types, mainly through deletion, loss of heterozygosity and promoter region hypermethylation. This includes cancers derived from reproductive tissues including cervical, prostate and ovarian germ-line tumours. Recent functional studies have also supported the theory that the SLITs and ROBOs have tumour suppressor activities. The SLIT/ROBO pathway promoted programmed cell death and/or reduced proliferation of fibrosarcoma, oesophageal, hepatocellular, colorectal, prostate and breast carcinoma cells. SLIT2 also inhibited the invasion of numerous different types of tumour cells including those from the prostate, breast, endometrium and ovary. The SLIT/ROBO pathway has now also been shown to have physiological roles in normal reproductive tissues. SLIT/ROBO signalling seems to regulate placental angiogenesis and trophoblast function in an autocrine and/or paracrine manner. In addition, most of the SLITs and ROBOs are also temporally regulated during the normal menstrual cycle in the endometrium and are expressed in the fallopian tube. Furthermore there is increased expression of the SLITs and ROBOs in the adult corpus luteum during the late-luteal phase of the ovarian cycle. At this time the SLIT/ROBO interaction may act to promote its disintegration by stimulating apoptosis and inhibiting migration of luteal cells. In the corpus luteum and endometrium expression of SLITs and ROBOs are hormonally regulated. There was reduced SLIT/ROBO expression in the decidualised endometrium of early pregnancy. In addition the luteotrophic molecules, human chorionic gonadotrophin and cortisol, that are increased in early pregnancy, reduce the expression of SLITs and ROBOs in luteal cells. Around 90% of ovarian malignancies are classified as epithelial tumours that are thought to derive from the ovarian surface epithelium. The risk of ovarian cancer is positively correlated with the number of ovulations. Thus recurrent injury and subsequent repair of the OSE during ovulation may predispose this tissue to neoplasia.