Abstract 457: Satisfying the fatty acid demand of prostate cancer: Outlier overexpression of genes involved in de novo synthesis vs fatty acid uptake define two different and potentially synergistic prostate cancer phenotypes
Authors: Gaston Sandra M. , Kearns James , Adams George W. , Rais-Bahrami Soroush , Nix Jeffrey W. , Kolettis Peter N. , Bryant James E. , DeGuenther Mark S. , Oelschlager Denise , Otali Dennis , Grizzle William E. 
Published: July 2017

Malignant transformation increases cellular demand for fatty acids (FA). Many cancers, including prostate cancer (PCa), show increased expression of fatty acid synthase (FASN), the enzyme that catalyzes the de novo synthesis of the FA palmitate. De novo FA synthesis is energetically expensive; in most normal cells FASN expression is low and de novo synthesis suppressed in favor of utilization of exogenous FA. In contrast, in cancer cells, de novo FA synthesis is an important source of precursors needed to support tumor growth. Much of the research effort on FA in cancer has focused on FASN and the other genes involved in de novo FA synthesis. However a number of observations suggest that alternate mechanisms for FA acquisition are also important, most notably studies showing that cancer cells can be rescued from the pro-apoptotic effect of FASN inhibition by exogenous palmitate. Using a biopsy-based approach designed to identify high risk prostate cancer phenotypes that are common in African American (AA) men, we identified a PCa subtype with outlier (&gt; 10 fold) mRNA overexpression of fatty acid binding protein 5 (FABP5). FABP5 facilitates the utilization of palmitate and other FAs from outside the cell, and a FABP5 overexpression phenotype may confer a selective advantage when dietary FAs are abundant or when FASN is targeted as a therapy. The FABP5 outlier overexpression phenotype was observed in 7% Gleason sum (GS) 7-10 PCas. We also observed a second molecular subtype with outlier FASN overexpression in 9% of GS 7-10 PCas. With few exceptions these two PCa subtypes showed an “either-or” pattern with top quartile overexpression of FABP5 or FASN but not both (Spearman r = 0.385; P &lt; 0.0001). Interestingly, in low grade (GS 6) PCas, median FABP5 mRNA overexpression is higher in AA than in European American (EA) men (P &lt; 0.01) with GS6 PCas from AA men showing median FABP5 expression levels as high as that observed in GS 7-10 PCas. IHC confirmed variable expression of both FABP5 and FASN, including “patchwork” PCas with high Gleason pattern (GP) areas overexpressing FABP5 next to low GP areas overexpressing FASN. The net result may be a selective advantage for the high grade cancer if FABP5 allows it to exploit the FA being synthesized by the adjacent low grade focus. In a subset of PCas, FABP5 IHC showed robust nuclear staining consistent with its proposed role in regulating fatty acid mediated gene expression; the ratio of FABP5 nuclear/cytoplasmic staining was higher in PCa from AA than from EA patients (P &lt; 0.05). Identification of a PCa subtype with high levels of FABP5 overexpression suggests a previously unrecognized mechanism by which some PCas can increase FA supply without de novo synthesis. Such a PCa subtype might be particularly sensitive to dietary interventions and relatively insensitive to FASN inhibitors.

Citation Format: Sandra M. Gaston, James Kearns, George W. Adams, Soroush Rais-Bahrami, Jeffrey W. Nix, Peter N. Kolettis, James E. Bryant, Mark S. DeGuenther, Denise Oelschlager, Dennis Otali, William E. Grizzle. Satisfying the fatty acid demand of prostate cancer: Outlier overexpression of genes involved in de novo synthesis vs fatty acid uptake define two different and potentially synergistic prostate cancer phenotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 457. doi:10.1158/1538-7445.AM2017-457