FOXA2 PROMOTES PROSTATE CANCER BONE COLONIZATION

Abstract

BackgroundIt is estimated that 26,000 men will die from prostate cancer (PCa) in 2017. Androgen deprivation therapy (ADT) is the gold standard treatment for advanced PCa. Initially, patients respond to treatment, however, these tumors almost invariably progress to castrate‐resistant PCa, for which there is no cure. Most PCa patients who fail ADT develop metastasis and preferentially relocate to the bones. Bone metastasis results in significant morbidity and mortality as the average time to death is approximately 3–5 years with no treatment available. Understanding the mechanisms by which PCa grow in the bone is critical for the development of novel therapeutics to treat and decrease tumor‐mediated bone destruction.MethodsGene expression profiling studies have found that FOXA2, a forkhead transcription factor that is expressed in embryonic prostate and neuroendocrine PCa, is present in a subset of metastatic PCa specimens. Our preliminary study found FOXA2 expression in a sample set of human PCa bone metastases, suggesting an involvement of FOXA2 in human PCa bone metastases. Also, we found high levels of FOXA2 in aggressive PCa PC3 cells, but not in PCa LNCaP cells. PC3 cells generate osteolytic lesions in bone, whereas LNCaP cells minimally grow following bone inoculation. To establish FOXA2's role in promoting PCa metastasis, FOXA2 was stably knocked down in PC3 cells and overexpressed in LNCaP cells.ResultsWe found that FOXA2 knockdown in PC3 cells resulted in a significant decrease in PC3 mediated in vivo bone destruction following intra‐tibial injection. To understand how FOXA2 is facilitating these changes, we examined the expression of integrins and observed that FOXA2 knockdown decreased the expression of collagen‐binding integrins α1 and αv in PC3 cells. Furthermore, we found FOXA2 knockdown decreased PC3 cells' adhesion and spreading on collagen I (a major component of bone ECM) coated surfaces. The Foxa2‐controlled expression of integrins α1 and αv and the resulting changes in the adherence and spreading would provide a mechanism for PCa cells colonize bone and initiate the bone‐destruction cycle. Additionally, FOXA2 knockdown in PC3 cells resulted in a significant decrease in expression of parathyroid hormone‐related protein (PTHrP), a bone remodeling‐associated protein. We observed that PTHrP mRNA was decreased in FOXA2 knockdown cells and protein in FOXA2 knockdown subcutaneous grafts. When PC3 FOXA2 knockdown cells were co‐cultured with osteoblast and osteoclast, osteoclast markers were decreased.ConclusionsTaken together, FOXA2 plays a major role in facilitating PCa's ability to colonize bone, and further, promote osteoclast activation.Support or Funding InformationFeist‐Weiller Cancer Center/Foundation of Legacy Funds The Office of Research SEED awardsThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.