The Role of RUNX Transcription Factors in Prostate Development and Tumorigenesis

Abstract

Prostate cancer is the most prevalent malignant neoplasia affecting men over 65 years of age. While prostate carcinoma is considered mostly curable when confined to the prostatic capsule, more aggressive forms have a predilection to metastasise to the bone. Increased expression of RUNX2 in primary tumours has been proposed to promote bone metastasis due to its critical role in bone regulation. However a role in tumour development and progression remains to be elucidated for RUNX2, or its β-subunit, CBFb. This thesis examines a role for RUNX2 during prostate cancer progression and defines a novel role for CBFβ and the RUNX-associated transcriptional repressor, ETO in prostate development and tumorigenesis. ETO was differentially expressed during prostate development and tumorigenesis, in vivo. Additionally, in vitro, ETO protein expression was confirmed in all prostate cancer cell subtypes, with high expression associated with aggressive, metastatic prostate cancer cells. Manipulation of ETO in vitro demonstrated a requirement for ETO in the growth and invasion of human prostate cancer cells. Subsequent examination of these cells in subcutaneous xenograft models revealed a requirement for ETO in aggressive tumour growth in vivo. Examination of CBFβ in vivo, demonstrated its differential expression during prostate development and tumorigenesis. CBFβ knockdown in an aggressive prostate cancer cell line demonstrated that CBFβ expression was required for growth and invasion in vitro and delayed tumour growth following in vivo xenograft examination. RUNX2 was shown to promote increased cell growth and invasion in human prostate cancer cells in vitro. Subsequent in vivo examination of a non-aggressive prostate cancer cell line following forced RUNX2 expression demonstrated decreased primary tumour growth but was associated with increased metastasis. These data provide a new role for ETO and CBFβ in prostate development and tumorigenesis and a novel role for RUNX2 in the phenotypic shift associated with metastatic prostate cancer.