Using the "reverse Warburg effect" to identify high-risk breast cancer patients: Stromal MCT4 predicts poor clinical outcome in triple-negative breast cancers

Agnieszka K. Witkiewicz, Diana Whitaker-Menezes, Abhijit Dasgupta, Nancy J. Philp, Zhao Lin, Ricardo Gandara, Sharon Sneddon, Ubaldo E. Martinez-Outschoorn, Federica Sotgia, Michael P. Lisanti

    Research output: Contribution to journalArticlepeer-review

    Abstract

    We have recently proposed a new model of cancer metabolism to explain the role of aerobic glycolysis and L-lactate production in fueling tumor growth and metastasis. In this model, cancer cells secrete hydrogen peroxide (H 2O2), initiating oxidative stress and aerobic glycolysis in the tumor stroma. This, in turn, drives L-lactate secretion from cancer-associated fibroblasts. Secreted L-lactate then fuels oxidative mitochondrial metabolism (OXPHOS) in epithelial cancer cells, by acting as a paracrine onco-metabolite. We have previously termed this type of two-compartment tumor metabolism the "reverse Warburg effect," as aerobic glycolysis takes place in stromal fibroblasts, rather than epithelial cancer cells. Here, we used MCT4 immunostaining of human breast cancer tissue microarrays (TMAs; >180 triple-negative patients) to directly assess the prognostic value of the "reverse Warburg effect." MCT4 expression is a functional marker of hypoxia, oxidative stress, aerobic glycolysis and L-lactate efflux. Remarkably, high stromal MCT4 levels (score = 2) were specifically associated with decreased overall survival (
    Original languageEnglish
    Pages (from-to)1108-1117
    Number of pages9
    JournalCell Cycle
    Volume11
    Issue number6
    DOIs
    Publication statusPublished - 15 Mar 2012

    Keywords

    • Caveolin-1, oxidative stress
    • Lactate shuttle
    • MCT4
    • Metabolic coupling
    • Predictive biomarker
    • Pseudohypoxia
    • SLC16A3, monocarboxylic acid transporter
    • Tumor stroma
    • Two compartment tumor metabolism

    Fingerprint

    Dive into the research topics of 'Using the "reverse Warburg effect" to identify high-risk breast cancer patients: Stromal MCT4 predicts poor clinical outcome in triple-negative breast cancers'. Together they form a unique fingerprint.

    Cite this