Function of the Cyclin D1b oncogene in cancer progression: Mechanisms and implications
Prostate cancer (PCa) represents the most commonly diagnosed non-cutaneous malignancy in men and remains a leading cause of cancer related deaths in this population worldwide. While localized disease can be effectively treated/managed though radical prostatectomy and/or radiation therapy, disseminated disease represents much more of a clinical challenge. Through nearly a century of research, the androgen receptor (a ligand dependent nuclear receptor) has been identified as a critical driver of tumor development and progression at all stages of disease. As such, targeted inhibition of this pathway represents the most effective method to thwart progression of advanced and metastatic disease. While multiple therapeutics options have been developed to target this critical signaling node (ranging from systemic hormonal therapy, to direct antagonism of AR itself), tumors resistant to this class of therapy ultimately arise, with no form of durable treatment available at this stage. Consequently, a concerted effort has been put forth to understand the molecular underpinnings of the AR signaling pathway and collaborative networks which contribute to advanced disease phenotypes and therapeutic resistance. Work herein will describe the cross talk between the pro-oncogenic nuclear receptor cofactor Cyclin D1b, and AR driven networks that cooperate to promote advanced tumor phenotypes in prostate cancer, and describe the functional consequences of the switch to Cyclin D1b on development, tumor formation, and therapeutic response. Collectively, these studies utilized models derived from cell culture systems, subcutaneous xenografts, and a novel knock-in murine line. Techniques encompassing, biochemistry, molecular biology, histology, pathology, pharmacology, and genetics were utilized to interrogate the stated hypotheses. Utilizing data collected, it will be concluded that Cyclin D1b induction is associated with markers of cellular stress, functions in concert with AR driven networks to drive advanced tumor phenotypes, and unmasks novel therapeutic options to treat and manage tumors harboring this disease specific isoform.
Augello, Michael A, "Function of the Cyclin D1b oncogene in cancer progression: Mechanisms and implications" (2014). ETD Collection for Thomas Jefferson University. AAI3705003.