Developmental Research Pilot Project

Joshi Alumkal, MD, Oregon Health & Science University

"Elucidation of novel mechanisms of sulphoraphane chemoprevention in a murine model"

Abstract

Prostate cancer remains the most common cancer in men in the United States. The androgen receptor (AR) is the key growth factor signaling pathway in prostate cancer, and one of its target genes ERG is commonly over-expressed in human prostate cancer. Recent work by our collaborators from FHCRC using an ERG transgenic murine model, which recapitulates the AR-regulated ERG expression seen in human prostate cancer, showed that ERG over-expression transforms normal prostate cells and leads to PIN, prostatic intraepithelial neoplasia, a prostate cancer precursor lesion.

Sulforaphane is an isothiocyanate compound found in broccoli, and this compound has been shown to be an effective chemopreventive agent in innumerable animal model systems. In addition, high consumption of broccoli is associated with a reduced risk of prostate cancer. Our recent work demonstrates that sulforaphane treatment of prostate cancer cells reduces protein levels of AR and consequently ERG. We believe these findings may have mechanistic implications for prostate cancer prevention with sulforaphane or high intake of broccoli.

Our long-term goal is to identify a new approach to prevent and treat prostate cancer and the mechanisms thereof. Our central hypothesis is that sulforaphane treatment of mice with AR-regulated ERG over-expression will ablate AR and ERG expression and that this will prevent transformation of normal prostate cells. Our aims are two-fold:

1. To determine whether supplementation of ERG transgenic mice with sulforaphane reduces AR and ERG expression in the setting of HDAC inhibition, and
2. To determine whether supplementation of ERG transgenic mice with sulforaphane also reduces the incidence of PIN.

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