Presenting Author:

Bing Song, Ph.D.

Principal Investigator:

Jindan Yu

Department:

Medicine

Keywords:

FOXA1, TGFB, EMT, prostate cancer

Location:

Third Floor, Feinberg Pavilion, Northwestern Memorial Hospital

B55 - Basic Science

Targeting FoxA1 mediated pathways in Castration Resistant Prostate Cancer

Targeting FoxA1 mediated regulation of TGFβ and AR pathways in Castration Resistant Prostate Cancer Prostate Cancer is the second leading cause of cancer-related death in men in the United States. FOXA1 is a well-known pioneering transcription factor and co-activator of the androgen receptor (AR), indispensable for the lineage-specific gene expression in the prostate. However, in contrast to its conventional proliferative role, the function of FOXA1 as a tumor suppressor in prostate cancer is far from understood. Here, we reveal that FOXA1 negatively regulates TGFB3 by directly binding to its enhancer. FOXA1 loss induces TGFβ signaling which leads to epithelial-to-mesenchymal transition (EMT) and cell invasion in prostate cancer cells. The increased cell invasiveness can be effectively blocked by TGFβ signaling inhibitor. More importantly, we found that pSMAD2 which represents the activation of downstream target of TGFβ signaling has been significantly increased in the enzalutamide resistant prostate cancer cell line possibly caused by FOXA1 loss. Combination of enzalutamide and TGFβ signaling inhibitor have a synergistic effect on inhibiting prostate cancer cell proliferation and invasion in vitro and in vivo. This study greatly extends our knowledge on AR-independent roles of FOXA1, and provide novel therapeutic strategies for treatment of castration-resistant prostate cancer.