Defining genetic and metabolic requirements of aggressive breast cancer

点击翻译按钮获取中文摘要

ABSTRACT While mortality rates for breast cancer (BC) have dropped precipitously over the past few decades due primarily to advances in treatment and detection, more than 42,000 individuals in the US will still die of this disease in 2019. These BC deaths are largely attributed to recurrent and metastatic disease. While classifiers such as ER positivity and HER2 status provide insights into BC prognosis and treatment, local and distal BC recurrence occurs across all BC subtypes. Due to our current inability to predict or prevent BC recurrence, BC is one of the most overtreated diseases with patients undergoing extended rounds of chemotherapy and treatment that may provide only marginal benefit. This is especially evident with ER+ (luminal) BCs where long term treatment with hormonal therapies is recommended for many patients, despite side effects, as a result of our inability to effectively predict the risk of late recurrence within this group. As such, there is a clear need to better understand the biology of BC recurrence and to devise a means to treat and/or prevent BC progression. Toward this goal, we have identified the RON receptor tyrosine kinase and the nuclear DEK oncogene as a signal transduction axis whose upregulation promotes BC growth and supports BC stem-like cell (BCSC) populations, which are considered a prime driver of recurrent and metastatic disease. Clinically, RON and DEK are frequently overexpressed in BC and their combined expression is highly predictive of BC recurrence, distant metastasis and death in patients across all human BC subtypes. We previously reported that high RON-DEK levels are strongly associated with β-catenin accumulation in human BC samples and that β-catenin is a synergistically activated target of RON and DEK. Recent discoveries in our laboratories show that RON or DEK overexpression increase the levels of key enzymes required for glycolysis, lactate production, and for cholesterol biosynthesis. We further show that RON and DEK expression increase glycolytic flux consistent with new studies highlighting metabolic shifts in response to β-catenin activation. Based on this data, we hypothesize that RON-DEK signaling acts, at least in part, through β-catenin to reprogram metabolic flux for sustaining the energy and macromolecule synthesis required for BC progression. Thus, the goal of this application is to determine the mechanistic roles of β-catenin and metabolic reprograming in RON/DEK-driven BC recurrence, and to define and therapeutically block metabolic effectors of this signaling axis to prevent BC progression and recurrence. Metabolic flux studies will be carried out in syngeneic animal models of BC and in live human BC specimens. These studies will be performed by a team of scientists and clinicians, and include a renowned expert in stable isotope resolved metabolomics approaches, that will be utilized to define RON/DEK dependent anabolic/catabolic processes. This untargeted approach is expected to identify candidate biomarkers and effectors of aggressive tumors with high RON/DEK expression. The supposition is that targeting vulnerable nodes of the RON/DEK metabolic signature will be an efficacious strategy for the treatment of advanced BC phenotypes.