ELUCIDATING THE ROLE OF PRIMARY CILIA AS PUTATIVE TUMOR SUPPRESSORS IN THE PROSTATE AND BREAST

Abstract

Prostate and breast cancer are among the most commonly diagnosed cancers and leading causes of cancer-related deaths in men and women worldwide. It is therefore evident that enhanced understanding of tumorigenesis is required to improve diagnostic tools, improve prognostics and identify novel therapeutic targets. The goal of this dissertation was to elucidate the role of primary cilia in prostate and breast cancer. Little is known about the role primary cilia may play in these cancers. Primary cilia are microtubule-based organelles which aid in sensing the extracellular environment and participate in signal transduction. Important developmental signaling pathways, such as Hedgehog (Hh) and Wnt signaling pathways, involve cilia. These pathways have also been implicated in prostate and breast cancer. In this work, we demonstrate that cilia are lost through prostate cancer progression. The few remaining cilia on prostate cancers appeared to be dysfunctional, as assessed by quantifying cilia lengths, an indirect measure of functionality. We also investigated a link between the observed cilia loss and canonical Wnt signaling in prostate cancers. Primary cilia have been determined to have a suppressive role in Wnt signaling, therefore we predicted loss of cilia to correlate with increased Wnt signaling. A link between cilia loss or shortened cilia and activated Wnt signaling was suggested in a subset of prostate cancers. Our lab has established that cilia are similarly lost in breast cancer. These data suggested the hypothesis that cilia may act as tumor suppressor organelles in the prostate and breast. To test this hypothesis, we knocked down cilia in an oncogenic mammary mouse model and assessed changes in tumor growth and characteristics. We observed enhanced tumor growth with cilia loss. The data supports the hypothesis that primary cilia may be playing a tumor suppressor role in the prostate and breast, and provides promising avenues for identifying novel therapeutic approaches for cancer patients.