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Dissertation/Thesis Abstract

Developing Pre-Clinical Mouse Models of Prostate Cancer: Deciphering the Roles of Tumor Suppressors Adenomatous Polyposis Coli and Smad4
by Valkenburg, Kenneth C., Ph.D., Van Andel Research Institute, 2014, 254; 10274873
Abstract (Summary)

There are approximately 230,000 new diagnoses of prostate cancer every year in the U.S., making prostate cancer the most diagnosed cancer in men. It is responsible for approximately 30,000 deaths per year, with only lung cancer taking more lives. An important distinction must be made in men with prostate cancer. The majority of men with prostate cancer have a relatively indolent form of the disease, meaning high survival rates (100% survival 5 years after diagnosis) and no invasion of the tumor to other organs. However, approximately 4% of men are diagnosed with an aggressive form of the disease, and for these men, the survival rate is a mere 30% after 5 years. And for many patients, it is clinically difficult to differentiate between the indolent and the aggressive forms of the disease. Therefore, it is imperative to develop new genetic models of prostate cancer, and the mouse is an excellent model organism in which to do so. In 2009, mice were used to discover a new type of stem cell, called a castration-resistant Nkx3.1-?expressing cell in the luminal cell population of the prostate. We have used a mouse model targeting these cells to study the roles of two tumor suppressors, adenomatous polyposis coli (Apc) and Smad4. Apc down-regulates the Wnt signaling pathway, which is a carcinogenic pathway in the prostates of humans and mice. Deletion of Apc in mice causes an increase of Wnt signaling and prostate cells to proliferate but not invade, which represents a relatively indolent, precancerous phenotype. Smad4 is a transcription factor that controls the signaling of two pathways: transforming growth factor β and bone morphogenetic protein signaling. Deletion of Smad4 causes these pathways to shut off. When Apc and Smad4 are deleted simultaneously, mice develop aggressive, invasive prostate cancer. This work suggests that these two tumor suppressors – and the pathways they control – are important regulators of prostate cancer, could allow for clinicians to differentiate between indolent and aggressive disease, and should be targeted therapeutically in prostate cancer patients.

Indexing (document details)
Advisor: Williams, Bart
Commitee: Bushman, Wade, Miranti, Cindy, Prins, Gail, Steensma, Matt
School: Van Andel Research Institute
Department: Biomedical
School Location: United States -- Michigan
Source: DAI-B 78/11(E), Dissertation Abstracts International
Subjects: Molecular biology, Genetics, Oncology
Keywords: Adenomatous polyposis coli, Prostate cancer, Smad4
Publication Number: 10274873
ISBN: 978-1-369-88287-2
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