Macrophage/Prostate Cancer Cell Interactions Trigger a Molecular Mechanism For SARM Resistance

Abstract

Prostate cancer is the most frequently diagnosed malignancy in males in the USA. Currently available Selective Androgen Receptor Modulators (SARMs; AR antagonists), which repress AR-mediated transcription of target genes such as PSA, are initially effective in controlling tumor growth. However, most patients develop resistance to these drugs due to incompletely investigated mechanisms. Macrophages, despite beneficial roles in immune surveillance and wound healing, contribute to various pathologies, such as atherosclerosis and obesity-associated insulin resistance. In this study, we employed tissue arrays, macrophage-binding assays, mouse genetics, single-cell nuclear microinjection and real-time RT-PCR to address the potential role of macrophages in anti-androgen resistance in prostate cancer. Here, we report that macrophage/cancer cell interactions cause a switch in function of SARMs from repression to activation of AR-mediated transcription. After uncovering the molecular mechanism underlying this switch, we were able to generate a molecule that blocked SARM resistance in vitro. Our results point to a key role of the immune system in regulating steroid hormone receptor function in the tumor microenvironment and provide a potential therapeutic strategy for overcoming inflammation-induced SARM resistance. NIH-CA- 97134, DoD-PCRP-W81XWH.