Project:
Therapeutically Targeting Novel Metabolic Activities of Basal and Luminal Breast Tumors

Principal Investigator - Luika Timmerman, PhD

ABSTRACT

These studies arise out of the analysis of a large set of expression profiling data derived from various types of human breast epithelial and tumor samples. This includes purified, normal luminal and basal breast epithelial cells; samples taken directly from patient pleural effusions; and a large panel of established breast cancer cell lines and immortal non-tumorigenic cell lines now referred to as the ICBP45 panel. The expression profiles revealed that breast tumors overexpress hundreds of metabolic enzymes relative to normal breast epithelial cells, and we have set out to understand how these differences can be leveraged to produce novel therapeutics that target tumor metabolism. Our early data directly challenges the hypothesis put forth by Otto Warburg which drives current tumor metabolism research: that enhanced ATP production is required for incremental tumor "aggressiveness" - proliferation rate and disease progression, and relies upon coincident increases in glucose consumption and lactate production to offset mitochondrial functional defects. Instead, we find that breast tumors can be grouped into two distinct metabolic classes based on glucose consumption rate and response to nutrient deprivation. Tumors which most avidly trap glucose comprise a subset of "luminal"-type breast tumors and overexpress a novel, high affinity glucose transporter. Surprisingly, these cells proliferate extremely slowly, produce little lactate, and maintain functional mitochondria. In contrast, many cell lines derived from, and which mimic the more aggressive "basal"-type breast tumors consume comparatively little glucose and appear relatively resistant to the effects of culture in glucose-free media. These cells proliferate rapidly and produce more lactate than the luminal, glucose-avid subset. A subset of these latter tumors is exquisitely sensitive to manipulation of other ambient nutrients and we are working hard to uncover the molecular mechanism for this sensitivity, with the aim of developing therapeutics which target these tumor types. Most strikingly, our data overturns currently held views of tumor metabolism, and significantly alters the way we think about metabolism-based therapeutics. It uniquely reveals that different subtypes of tumors within a particular organ system may enact completely distinct metabolic activities which present distinct therapeutic opportunities, and produces both a functional and therapeutically-valuable classification of human breast cancer.