Triple Negative Breast Cancer and Metabolic Regulation

Abstract

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 better 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) trigger an increase in both Wnt and EGFR signaling to regulate proliferation and senescence; and 2) were coincident with exceptional increased tumor growth and invasiveness in preclinical models of breast cancer. Our new data show that HBP1 levels are significantly reduced in TNBC relative to other breast cancer subtypes in clinical specimens. Strikingly, a new combined EGFR and HBP1 gene signature predicted 90+% of TNBC patients in 4 large patient databases and 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 several hundred genes to enact a Warburglike 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. This grant seeks to understand how HBP1, EGFR and Wnt signaling trigger metabolic reprogramming in the context of TNBC.