Selective overexpression of Human epididymal secretory protein E4 (HE4) points to a role in ovarian cancer tumorigenesis but little is known about the role the HE4 gene or the gene product plays. Here we show that elevated HE4 serum levels correlate with chemoresistance and decreased survival rates in EOC patients. HE4 overexpression promoted xenograft tumor growth and chemoresistance against cisplatin in an animal model resulting in reduced survival rates. HE4 displayed responses to tumor microenvironment constituents and presented increased expression as well as nuclear translocation upon EGF, VEGF and Insulin treatment and nucleolar localization with Insulin treatment. HE4 interacts with EGFR, IGF1R, and transcription factor HIF1α. Constructs of antisense phosphorothio-oligonucleotides targeting HE4 arrested tumor growth in nude mice. Collectively these findings implicate increased HE4 expression as a molecular factor in ovarian cancer tumorigenesis. Selective targeting directed towards the HE4 protein demonstrates therapeutic benefits for the treatment of ovarian cancer.

Tumor production of vascular

Sprouty family proteins are novel regulators of growth factor actions. Human Sprouty 2 (hSPRY2) inhibits the proliferation of a number of different cell types. However, the mechanisms involved in the anti-proliferative actions of hSPRY2 remain to be elucidated. Here we have demonstrated that hSPRY2 increases the amount of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and decreases its phosphorylation. The resultant increase in PTEN activity is reflected in decreased activation of Akt by epidermal growth factor and serum. Consistent with increased PTEN activity, in hSPRY2-expressing cells, the progression of cells from the G 1 to S phase is decreased. By using PTEN null primary mouse embryonic fibroblasts and their isogenic controls as well as small interfering RNA against PTEN, we demonstrated that PTEN is necessary for hSPRY2 to inhibit Akt activation by epidermal growth factor as well as cell proliferation. Overall, we concluded that hSPRY2 mediates its anti-proliferative actions by altering PTEN content and activity.Over the past few years, the Sprouty (SPRY) 2 family of proteins has emerged as an important modulator of growth factor actions. The ability of the Sprouty proteins to regulate the biological activity of growth factors has been conserved through evolution. Drosophila SPRY (dSPRY) was the first member of the family to be identified and has been shown to regulate tracheal branching in response to fibroblast growth factor (1). Later studies demonstrated that dSPRY also inhibited the actions of EGF (2). Like dSPRY, mammalian SPRY isoforms (SPRY1-4) have also been shown to modulate growth factor-mediated actions. For instance, mouse SPRY2 expression resulted in increased lung branching morphogenesis (3). These findings suggest that SPRY proteins have conserved function to modulate respiratory morphogenesis. The ability of mouse SPRY4 to inhibit angiogenesis (4) and cause pulmonary hypoplasia as well as the ability of SPRY2 and SPRY1 to decrease uteretic branching and kidney development (5, 6) also demonstrates that the SPRY proteins play a profound role in regulating tubular morphogenesis. Notably, however, SPRY proteins do not exclusively regulate tubular morphogenesis, but by opposing the actions of growth factors they may also play a role in the development of other organs, such as the brain and limbs (7-9).At the cellular level, we and others have shown that overexpression of SPRY1 (10), SPRY2 (11, 12), and SPRY4 (5) inhibits migration and proliferation of cells in response to serum and growth factors. Treatment of cells with EGF results in translocation of the human SPRY2 (hSPRY2) protein from the vicinity of microtubules to membrane ruffles (11, 13). The abrogation of co-localization of hSPRY2 with microtubules or deletion of the region that is necessary for translocation to membrane ruffles obliterates the ability of the protein to inhibit cell migration and proliferation (11). We have shown previously that hSPRY2, in part, mediates its anti-migratory action...

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