Metabolic Profiling Reveals PAFAH1B3 as a Critical Driver of Breast Cancer Pathogenicity

Abstract

Many studies have identified metabolic pathways that underlie cellular transformation, but the metabolic drivers of cancer progression remain less well understood. The Hippo transducer pathway has been shown to confer malignant traits on breast cancer cells. In this study, we used metabolic mapping platforms to identify biochemical drivers of cellular transformation and malignant progression driven through RAS and the Hippo pathway in breast cancer, and identified platelet activating factor acetylhydrolase 1B3 (PAFAH1B3) as a key metabolic driver of breast cancer pathogenicity that is upregulated in primary human breast tumors and correlated with poor prognosis. Metabolomic profiling suggests that PAFAH1B3 inactivation attenuates cancer pathogenicity through enhancing tumor-suppressing signaling lipids. Our studies provide a map of altered metabolism that underlies breast cancer progression and put forth PAFAH1B3 as a critical metabolic node in breast cancer.

Methylglyoxal, a glycolysis side-product, induces Hsp90 glycation and YAP-mediated tumor growth and metastasis

“…We have previously reported MG-mediated carbonyl stress, assessed by argpyrimidine adducts detection, in a series of breast cancer lesions (Chiavarina et al, 2014). Recent reports highlighted the importance of glucose metabolism for the regulation of YAP activity in cancer cells (DeRan et al, 2014; Enzo et al., 2015; Mulvihill et al, 2014). To explore possible links between YAP activity and carbonyl stress, we performed immunohistochemistry staining of YAP on a series of 87 breast tumors categorized as high and low-to-intermediate carbonyl stress tumors based on their endogenous argpyrimidine level.…”

“…Enzo and collaborators (Enzo et al., 2015) have recently demonstrated that aerobic glycolysis impacts on YAP/TAZ transcriptional activity through a mechanism involving phosphofructokinase 1 binding to TEAD transcription factors. A recent metabolic profiling study using breast cancer progression cellular models reported the induction of several glycolytic enzymes upon constitutive activation of YAP/TAZ factors (Mulvihill et al, 2014). Therefore, it is tempting to speculate that MG could regulate key glycolytic enzymes expression in a YAP-dependent manner thus creating a mutual regulatory loop where glycolysis-induced MG stress favors YAP activity, which in turn activates glycolysis.…”

“…As a co-activator of TEAD family of transcription factors (Zhao et al, 2008), YAP has been notably shown to enhance cancer progression through transcriptional activation of proliferation promoting genes such as c-myc and CTGF (Moroishi et al, 2015). Recent studies established a link between glucose deprivation stress, aerobic glycolysis and YAP activation in cancer (DeRan et al, 2014; Enzo et al., 2015; Mulvihill et al, 2014). Thus, reinforcing the increasing evidence indicating that metabolic pathways play causative roles in conferring an aggressive phenotype upon cancer cells.…”

GSTP1 Is a Driver of Triple-Negative Breast Cancer Cell Metabolism and Pathogenicity

“…Metabolomic analyses were conducted using previously described methods (Benjamin et al, 2013, 2014,2015; Long et al, 2011; Mulvihill et al, 2014). More details can be found in Supplemental Methods.…”

Overview of PAF-Degrading Enzymes

“…Mulvihill et al conducted proteomic profiling and identified dysregulated metabolic pathways in a model of breast cancer progression and then used RNA interference-mediated knockdown to screen for dysregulated enzymes [34]. Knockdown of the expression of the α 1 and α 2 catalytic subunits of PAF-AH I markedly impairs proliferation, survival, and migration of breast cancer cells.…”