Abstract B030: The HBP1 transcriptional repressor: An unexpected window on breast cancer metabolism in triple-negative breast cancer
Authors: Yee Amy S. , Paulson Kurtz Eric , Wang Kai , Field Wesley , Pedro Brian , Vigneault Davis , Baleja James B. 
Published: May 2015

Abstract
Triple-negative breast cancer (TNBC) represents 20-25% of sporadic breast cancers, lacks ER, PR, and overexpressed Her2 – and thus has no targeted treatment options. TNBC is the most clinically challenging subtype with exceptionally poor prognosis, high recurrence and metastases and currently represents an unmet medical need. While classified pathologically by negative criteria, TNBC is a heterogeneous group of breast cancers in need of improved molecular classification. Numerous studies have linked EGFR signaling to TNBC, but paradoxically, TNBC is refractory to the well-used EGFR inhibitors that have been efficacious in other cancers. In addition, Wnt signaling has been linked to TNBC, but its relationship to EGFR signaling and inhibitor resistance has not been explored. In the current work, the HBP1 transcriptional repressor may be a new and unappreciated bridge to both TNBC pathways. Previously, we have shown that decreases in HBP1: 1) triggered an increase in both Wnt and EGFR signaling to regulate proliferation and senescence; 2) were coincident with exceptional increased tumor growth and invasiveness in preclinical models of breast cancer; and 3) were associated with a poor breast cancer prognosis.
While altered metabolism has been investigated in many cancers, the mechanisms by which EGFR and Wnt signaling might trigger a metabolic reprogramming have not been investigated in TNBC. Our data suggests that HBP1 may be a new integrating factor. Our new data show that HBP1 levels are significantly reduced in TNBC relative to other breast cancer subtypes in clinical specimens. We derived a new combined EGFR and HBP1 gene signature that predicted 90+% of TNBC patients in 4 large patient databases and additionally predicted a poor patient prognosis in non-TNBC patients. To understand how HBP1 decreases trigger a poor prognosis, a whole genome analysis revealed a surprising change in 300+ genes to enact a Warburg-like metabolic reprogramming. The Warburg effect is characterized by increased glycolytic flux with increased biosynthesis of amino acids, lipids, and nucleic acids'all to provide for the increased growth and proliferation demands of a tumor cell. The specific pattern was an increase in certain isoforms involved in glycolysis and TCA cycle and a decrease in the expression of genes involved in oxidative phosphorylation. We used gene-, biochemistry- and NMR-based approaches to investigate the metabolic alterations upon changes in HBP1 expression in TNBC cells and tumors. Our results show that hexokinase 2 (HK2), Pyruvate Kinase-M2 (PKM2), Lactate Dehydrogenase A (LDHA), malate dehydrogenase 2 (MDH2) are amongst the metabolic enzymes that are altered with HBP1 expression and with increased Wnt signaling. HK2, PKM2, LDHA and MDH2 have all been previously associated with the Warburg effect. The NMR and biochemical analysis showed that lactate and fumarate are amongst the metabolites that are altered. The results here provide important metabolomics information to impact MRI/MRS studies. While breast MRIs are used for assessing tumor morphology, MRS (magnetic resonance spectroscopy) methods can non-invasively visualize metabolic spectra in tumors or metastases. The metabolic changes from our studies potentially focus MRS/MRI applications for the future discovery of non-invasive MRS biomarkers to improve TNBC classification and treatment efficacy. (Supported by a grant to ASY and JB from the Dept. of Defense).
Citation Format: Amy S. Yee, Kurtz Eric Paulson, Kai Wang, Wesley Field, Brian Pedro, Davis Vigneault, James B. Baleja. The HBP1 transcriptional repressor: An unexpected window on breast cancer metabolism in triple-negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B030.