This project aims to systematically investigate the biological functions and molecular regulation of LRIG1 in prostate cancer (PCa) development and in castration-resistant PCa (CRPC). Why is this important and significant? LRIG1 (leucine-rich repeats and immunoglobulin-like domains protein 1) is frequently downregulated/lost and functions as a tumor suppressor in many cancers. Furthermore, LRIG1 plays a critical role in regulating the quiescence of adult (epidermal and intestinal) stem cells. In both settings, LRIG1 enforces SC quiescence and inhibits tumor development via promoting degradation of and antagonizing mitogenic signaling from the ERBB and related protein tyrosine kinases. Despite this critical body of knowledge on LRIG1, little is known and few papers have been published about LRIG1 functions and regulation in PCa. Our preliminary studies revealed a surprising finding: in contrast to its downregulation or loss in many cancers, LRIG1 mRNA and protein are significantly overexpressed in hundreds of PCa specimen examined. Strikingly, increased LRIG1 levels correlate with better patient survival, implicating a tumor-suppressive function of LRIG1 in PCa. Indeed, extensive xenograft-based studies in multiple models provided strong support to PCa-suppressive functions of LRIG1. By developing a novel prostate-specific LRIG1 transgenic model, we further provide preliminary genetic evidence that LRIG1 overexpression suppresses tumorigenesis in both Hi-Myc and TRAMP models. Other important and novel preliminary findings demonstrate that: 1) LRIG1 downregulates endogenous Myc in PCa cells; 2) in treatment-nave PCa cells, AR directly and predominantly regulates LRIG1 gene transcription; 3) in CRPC, LRIG1 expression becomes heterogeneous, is reduced, but persists; 4) in CRPC, both AR and `stemness' factors may play important roles in regulating LRIG1 expression; and 5) LRIG1 exhibits `therapeutic' effects on established AR+ and AR- PCa models. Based on our preliminary observations, here we test our overarching hypothesis that LRIG1 functions as an AR- and stemness-regulated feedback tumor suppressor in PCa and CRPC, with three Specific Aims: 1) Investigate PCa-suppressive functions of LRIG1 and underlying mechanisms in genetic mouse models; 2) Elucidate molecular details of AR-regulated LRIG1 expression and functions in androgen-sensitive PCa; 3) Determine functions and regulation of LRIG1 in CRPC. We shall accomplish these aims by combining tumor studies in genetic mouse and xenograft models with mechanism-oriented cell biological, molecular, and biochemical approaches. Significance: This project fills a critical gap in our knowledge on the functions and regulation of LRIG1 in PCa. The impressive tumor suppressive functions of LRIG1 and its association with good patient survival suggest the potential use of LRIG1 expression as a prognostic biomarker. Finally, our preliminary therapeutic results support potential utility of developing novel LRIG1-based anti-PCa and anti-CRPC therapeutics.
This R01 project aims to elucidate the biological functions and molecular regulation of a tumor-suppressive molecule called LRIG1 in PCa. Accomplishing the goals of the project will fill a critical gap in our knowledge on an important endogenous tumor suppressor, and lay a foundation for developing LRIG1 into a diagnostic/prognostic biomarker and therapeutic agent.