Characterisation of Potential Novel Mammary Gland Oncogenes: Glial Cell Line-Derived Neurotrophic Factor (GDNF) & Stromal Cell-Derived Growth Factor 20 (SF20)

Abstract

Breast cancer is still the most prevalent malignancy with one of the highest mortality rates in women from western societies and the search for new therapeutic targets to strengthen the arsenal against this disease is ever present. In this thesis I have investigated the role of two secreted growth factors in mammary carcinoma progression: Glial cell line-Derived Neurotrophic Factor (GDNF) and Stromal Cell-Derived Factor 20 (SF20) or C19orf10. Neurotrophic factors play an essential role in the development and maintenance of the central and peripheral nervous systems. Recently, GDNF has been implicated in the progression of several malignancies including pancreas, glioma, ovarian and breast. Herein, I have demonstrated that forced expression of autocrine GDNF in mammary carcinoma cells significantly regulates cell migration and chemotaxis in vitro. This action was affected by cell line type, expression of GFRα co-receptors and ligand concentration. More so, I presented evidence that suggests this action may be mediated through the PI3K/AKT, Rho and Plasminogen Activator pathways. This invasive behaviour was also evident in vivo where GDNF overexpression promoted local invasion and colonisation of distant organs. In estrogen receptor positive mammary carcinoma cells, high GDNF levels also conferred a growth advantage in vitro and in vivo. This was facilitated by an ability to promote cell cycle transition in nutrient deprived environments. In estrogen receptor negative cells this advantage was only evident in distant metastases in vivo. Lastly, preliminary evidence supports a possible role in angiogenesis and regulation of cancer stem cell populations. Together, this suggests that GDNF and the GDNF pathway may play a functional role in mammary carcinoma progression, particularly during metastasis. Upon further investigation GDNF may provide avenues for cancer therapeutic invention. Little is known about the biology of SF20. However, recently it has been proposed as a mediator of autocrine hGH directed oncogenesis with a possible role in growth and motility. In this study I sought to confirm these observations, in addition to expanding our knowledge on its role in mammary oncogenesis. I demonstrated that SF20 is overexpressed in mammary carcinoma tumours and causes growth suppression due to increased apoptosis and a converse growth advantage during anchorage independent growth. However antagonistic studies were inconclusive. Additional studies utilising alternative models may lead to greater clarity around the role of SF20 in mammary carcinoma.