Endocrine Abstracts

The stromal compartment changes with cancer, with an emergence in activated fibroblasts. These stromal changes, which occur with cancer initiation and throughout progression, are known to influence the hallmarks of cancer and are becoming increasingly studied for prognostic and therapeutic purposes. Androgen receptor (AR) signalling in stromal cells is important in prostate cancer and these cancer stromal communications, yet the mechanisms underpinning stromal AR contribution to disease development and progression remain unclear. Using tissue microarrays from dual cores of benign and cancerous tissue from each of 64 patients, we found an association between low stromal expression of AR and the androgen regulated protein FKBP5 with increased prostate cancer specific mortality over 5-years post diagnosis. In prostatic fibroblasts, microarray and ChIP analysis revealed cell-lineage specificity in AR binding and signalling, potentially resulting from differential co-regulator and pioneer factor expression. The lineage specific AR-signalling culminates in control of proliferation, secretion of paracrine factors, adhesion, invasion, and ECM production. The resulting ECM environment is able to alter the genetic profile of cancer cells as well as being able to impede cancer cell migration and invasion. Proteomic analysis revealed a potential role for LOXL2, which when silenced, affects ECM pore size and cancer cell invasion, and the expression of which was associated with prostate cancer mortality. In conclusion, when AR is disrupted in the stroma, it creates an environment that enables cancer invasion influencing patient outcome, providing prognostic markers and therapeutic targets.

Presenting Author: Damien A. Leach, Department of Surgery and Cancer, Imperial College London, UK. Email: [email protected]