Cyclin D1: repercussions of AR control and alternative splicing in prostate cance

Thomas Jefferson University, Philadelphia PA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Prostate cancer (PCa) cells are dependent on androgen receptor (AR) function for growth and survival;this dependence is exploited in treatment of disseminated cancers, wherein ablation of AR activity is the first line of therapeutic intervention. While initially effective, recurrent tumors ultimately arise as a result of inappropriately restored AR function. AR is a master regulator of G1-S phase transitions in PCa, and interrogation of this mechanism led to the discovery of significant cross-talk mechanisms between the AR and cell cycle pathways. Cyclin D1 is a major effector of androgen action, and serves specialized functions in PCa that were delineated during the first funding period. Active AR induces cyclin D1 accumulation, thereby stimulating cyclin dependent kinase 4 (CDK4) activity and G1 progression. However, we and others showed that accumulated cyclin D1 binds and inhibits AR activity, thereby engaging a negative feedback loop to attenuate subsequent mitogenic response in AR-positive PCa cells. These actions of cyclin D1 contribute to the observed cell cycle dependence of AR activity in PCa, wherein AR activity is inversely correlated with cyclin D1 expression. Thus, cyclin D1 serves as a "rheostat" that controls the strength and duration of the androgen response. The achieved goals of the first funding period were to dissect the mechanism and regulation of this cross-talk pathway in PCa. Our published and unpublished data demonstrate that cyclin D1 is a major effector of AR activity, and acts through defined mechanisms to alter both AR activity and androgen-dependent proliferation in PCa. Moreover, we demonstrated that aberrations in this process facilitate unleashed AR activity. Thus, this renewal application is based on the hypothesis that abrogation of cyclin D1 transcriptional regulatory function promotes unchecked AR activity in PCa cells, and provides a mechanism to promote tumor development and/or progression. The present renewal application will directly challenge this concept by dissecting the molecular impact of cyclin D1 action (and aberrations thereof) under conditions associated with tumor progression (aim 1), defining the consequence of cyclin D1b, a splice variant of cyclin D1 that is deficient in AR control and is induced in PCa, on androgen mediated gene regulation (aim 2), and determining the oncogenic capacity of cyclin D1b in the prostate (aim 3). PUBLIC HEALTH RELEVANCE: Fatal prostate cancer arises as a result of inappropriate androgen receptor (AR) activity, a protein that controls the action of testosterone. We discovered that aberrations in a second gene product (cyclin D1) serve to promote unchecked AR activity and tumor growth. Here, we will determine molecular mechanisms through which cyclin D1 controls AR and determine the importance of this protein in prostate cancer, with the long term goal of devising new therapies to treat this deadly disease.