Essential Components of Cancer Education

Modern cancer therapy/care involves the integration of basic, clinical, and population-based research professionals using state-of-the-art science to achieve the best possible patient outcomes. A well-integrated team of basic, clinical, and population science professionals and educators working with a fully engaged group of creative junior investigators and trainees provides a structure to achieve these common goals. To this end, the structure provided by cancer-focused educational programs can create the integrated culture of academic medicine needed to reduce the burden of cancer on society. This summary outlines fundamental principles and potential best practice strategies for the development of integrated educational programs directed at achieving a work force of professionals that broadly appreciate the principals of academic medicine spanning the breadth of knowledge necessary to advance the goal of improving the current practice of cancer care medicine

Steroid Hormones and Cell Cycle Regulation

From the tissue culture dish to genetically modified mice, this volume explores the long recognized role of steroid hormones in regulating cell proliferation and differentiation. Many striking effects of steroid hormones are apparent during development and neoplasia and these topics are covered extensively. Several chapters address the pharmacological uses of steroid and related hormones, their analogs and antagonists in controlling growth of endocrine cancers. This book also highlights the complex role of cross talk between steroid hormones and signals initiated at the cell surface in the regulation of cell cycle in hormone responsive tissues

Antiproliferative Effect of Vitamin D in Prostate Epithelial Cells

In the last decade, vitamin D and vitamin D analogs have emerged as potential chemotherapeutic agents for the treatment of a variety of cancers. The anticancer activity of vitamin D-based regimens is due, in large part, to inhibition of cell growth and promotion of cellular differentiation. Consistent with these cellular actions, compelling population-based and epidemiologic studies support the protective effects of vitamin D against prostate and certain other cancers. Cell cycle regulation is central to vitamin D’s antiproliferative effects. This chapter focuses primarily on the mechanisms of this cell cycle inhibition in prostate cancer cells and, for illustrative purposes, also highlights vitamin D effects on gene expression and cell cycle in cells derived from other solid tumors. Understanding the fundamental principles of vitamin D synthesis, metabolism and action has led to novel vitamin D-based therapeutic strategies, which are illustrated here. Finally, the possible molecular basis for resistance to vitamin D-mediated growth inhibition is considered

Vav3, a Rho GTPase Guanine Nucleotide Exchange Factor, Increases during Progression to Androgen Independence in Prostate Cancer Cells and Potentiates Androgen Receptor Transcriptional Activity

Abstract The progression of prostate cancer from androgen dependence to androgen independence is often accompanied by enhanced androgen receptor (AR) transcriptional activity. We observed a marked increase in the expression of Vav3, a Rho GTPase guanine nucleotide exchange factor (GEF), during the progression of human prostate cancer LNCaP cells to the androgen-independent derivative, LNCaP-R1. GEFs activate Rho family GTPases by promoting the exchange of GDP for GTP. Reporter gene assays showed that Vav3 potentiated AR transcriptional activity, and knock down of Vav3 resulted in decreased AR transactivation. Vav3 also increased androgen-induced levels of prostate-specific antigen mRNA. Furthermore, Vav3 enhanced AR activity at subnanomolar concentrations of androgen. This finding is particularly relevant because low androgen levels may be present in prostate tissue of patients undergoing androgen deprivation therapy. Enhancement of AR activity by Vav3 required amino terminal activation function 1 (AF1) of AR; however, Vav3 did not interact with AR or increase AR levels. Neither GEF function nor the C-terminal domains of Vav3 were required for Vav3-mediated enhancement of AR activity; however, the pleckstrin homology domain was obligatory. These data show that Vav3 levels rise during progression to androgen independence and support continued AR signaling (even under conditions of low androgen) by a novel GEF-independent cross-talk mechanism

The kinesin KIF20A promotes progression to castration-resistant prostate cancer through autocrine activation of the androgen receptor

Prostate cancer that recurs following androgen-deprivation therapy is termed castration-resistant, which is incurable and is marked by reactivation of androgen receptor (AR) signaling. KIF20A, a kinesin with unique structural features, is overexpressed in human castration-resistant prostate cancer (CRPC) compared to androgen-dependent PC and benign tissue. KIF20A has well-described roles in mitotic processes, but it has a less characterized function in vesicle fission and trafficking within Golgi-driven secretory pathways. Stable expression of KIF20A in androgen-dependent PC cells promoted progression to CRPC through the activation of AR signaling in vitro and in vivo. KIF20A expression resulted in the secretion of autocrine factors in the conditioned media that activated AR and caused castration-resistant proliferation of naïve androgen-dependent cells. Pharmacologic disruption of vesicle biogenesis blocked KIF20A-driven castration-resistant proliferation of androgen-dependent PC. KIF20A depletion or treatment with the KIF20A-specific inhibitor, paprotrain, reduced CRPC. These data are the first to establish KIF20A as a driver of CRPC progression through AR activation and as a promising therapeutic target against CRPC

Abstract 1069: Vav3 enhances androgen receptor splice variant activity and is critical for castration resistant prostate cancer growth and survival

Abstract Advanced or metastatic prostate cancer is treated by androgen deprivation; however, patients inevitably relapse with castration resistant prostate cancer (CRPC) that grows independently of androgen. However, CRPC remains dependent on androgen receptor (AR) signaling, which includes constitutive, ligand–independent action of naturally occurring AR splice variants. For example, the AR splice variant AR3 (also termed AR–V7) is expressed in CRPC and is linked to poor prognosis. Vav3, a Rho GTPase guanine nucleotide exchange factor, is an AR coactivator that is up–regulated in human prostate cancer as compared to benign tissue as well as in pre–clinical models of CRPC. Vav3 confers castration–resistant growth to androgen–dependent human prostate cancer cells and increased expression has been linked to increased clinical biochemical relapse. Despite the importance of AR coactivators in promoting CRPC, the potential role of these regulatory proteins in modulating AR splice variant activity is unknown. We examined the contributions of Vav3 to AR activity in two CRPC cell lines that naturally express relatively high levels of Vav3 and AR3. Vav3 or AR3 knockdown greatly attenuated cell proliferation, soft agar growth and ligand–independent AR activity. Vav3 potently enhanced the transcriptional activity of AR3 and another clinically relevant AR splice variant ARv567es. Furthermore, Vav3 enhanced AR splice variant activity through a distinctly different mechanism than Vav3 coactivation of full length AR. Vav3 knockdown resulted in lowered nuclear AR3 levels while total AR3 protein and mRNA levels remained static. Conversely, overexpression of Vav3 resulted in increased nuclear AR3. Co–immunoprecipitation revealed that AR3 and Vav3 interact. These novel data demonstrating physical and functional interactions between Vav3, a unique AR coactivator, and an AR splice variant provide insights into the mechanisms by which Vav3 exploits and enhances AR signaling in the progression to CRPC. Citation Format: Stephanie Peacock, Cale D. Fahrenholtz, Kerry L. Burnstein. Vav3 enhances androgen receptor splice variant activity and is critical for castration resistant prostate cancer growth and survival. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1069. doi:10.1158/1538-7445.AM2013-1069</jats:p