PROJECT SUMMARY/ABSTRACT
Breast cancer is the most diagnosed cancer type and the second leading cause of cancer-related death in
women in the United States. For the receptor positive (RP) subtype comprising the majority of diagnoses,
clinical interventions have been largely effective in limiting associated mortality when compared with other
cancers. However, the remaining 20%, which comprise the triple-negative breast cancer (TNBC) subtype, lack
known therapeutic targets and are the most clinically challenging.
Cancers display altered metabolism upon carcinogenesis. However, the efficacy of targeting metabolism in
cancer depends upon understanding metabolic dysregulation in the context of a specific oncogene. Our lab
and others have shown that levels of c-MYC (MYC), a proto-oncogene that dynamically regulates numerous
cellular functions during transformation, are increased in a majority of TNBC. MYC is known to regulate
glucose and glutamine metabolism in cancer, but our lab has shown that MYC regulates another important
bioenergetic pathway, fatty acid oxidation (FAO), in TNBC. Models for MYC-overexpressing TNBC display
decreased bioenergetic metabolism and primary tumor growth upon inhibition of FAO, indicating novel reliance
on that pathway. Here, we propose to investigate how TNBC permit increased FAO.
Increased FAO necessitates alterations to fatty acid (FA) availability, and one fatty acid trafficking component,
fatty acid binding protein 5 (FABP5), is upregulated in TNBC in a MYC-dependent manner. FABPs are lipid
chaperones that bind cytosolic FA and other molecules, and can access a range of cellular compartments. Our
data indicate that FABP5 loss in MO-TNBC is sufficient to cause defects in cell metabolism and proliferation.
FABP5 may contribute to altered FAO and proliferation by facilitating increased FA supply at the mitochondria
to permit increased oxidation. We hypothesize that increased trafficking of FA to the mitochondria by FABP5
facilitates altered FAO in a MYC-dependent manner. Accordingly, we propose investigation of the cellular
biology and biochemistry of FA trafficking, FABP5 regulation and FAO in TNBC. Our strategy combines:
utilization of high-content microscopy to visualize FA trafficking in vitro, carbon-tracing studies to follow FA
metabolism in vivo and in vitro, mass spectrometry-based metabolomic analyses, pharmacological and genetic
perturbations of FA trafficking, and conditional and constitutive MO-TNBC cell lines and tumor models.
We expect that our investigation of mechanisms of FAO in MO-TNBC will advance understanding of how FA
metabolism is regulated in cancer, and may identify novel therapeutic targets for the treatment of this clinically
challenging breast cancer subtype.