Functional studies of SOX11 and T-STAR - Translation of tumor-associated genes into clinical and biological insight

Abstract: Cancer is a disease that will affect most of us during a lifetime. Although the survival of cancer patients has incresed due to better treatment and earlier diagnosis, the prevalance of the disease is still increasing. This increase in the number of cancer cases diagnosed will impose a challenge to the cancer care and higher costs for socitey. Personalized medicine aims at reducing these costs while at the same time improving the care for the patient, mainly by using a more individualized therapy, but also a more preventive cancer care and even earlier diagnosis. For example, a more indivivualized treatment can target specific genetic aberrations found in a patient, and avoid treating those patients who lack the aberrations and therefore will not respond. To accomplish the goals of personalized medicine, biomarkers that can divide patients into different subgroups are needed. The aim of this thesis was to explore SOX11 and T-STAR as potential biomarkers in cancer. I was also interested in the function of these proteins in the tumor tissues where they are specifically expressed. Immunohistochemistry on tissue microarrays was used to evaluate the expression of SOX11 and T-STAR in primary tumor tissues, and the expression was then correlated to survival in the patients. The function of the proteins was explored using RNA interference and overexpression experiements in cancer cell lines. The results from my studies are presented in five papers in this thesis. First, we could confirm the diagnostic role of SOX11 in mantle cell lymphoma (MCL). Second, I show the prognostic potential of this protein, as patients with high expression of SOX11 are associated with a better survival, both in MCL and high-grade epithelial ovarian cancer. In MCL, SOX11 could possibly complement the MCL international prognostic index MIPI , a prognostic biomarker already in use in this disease. Third, in both tumor types SOX11 functions as a tumor-suppressor in vitro. Regarding T-STAR, its expression is correlated with better outcome for breast cancer patients, and therefore shows potential as a prognostic biomarker. Our studies also show that T-STAR has a growth-inhibitory function in breast cancer cell lines. In conclusion, both SOX11 and T-STAR are biomarkers that could be used in personalized medicine to subgroup patients and potentially guide treatment decisions. Both proteins function as growth-inhibitors in vitro, which correlates to the better prognosis for the patients with tumors expressing the proteins in vivo.