TP53 Induced Glycolysis and Apoptosis Regulator and Monocarboxylate Transporter 4 Drive Metabolic Reprogramming With c-MYC and NFkB Activation in Breast Cancer

Authors

Megan E. Roche, Thomas Jefferson University
Ying-Hui Ko, Thomas Jefferson UniversityFollow
Marina Domingo-Vidal, Thomas Jefferson UniversityFollow
Zhao Lin, Thomas Jefferson UniversityFollow
Diana Whitaker-Menezes, Thomas Jefferson University
Ruth C. Birbe
Madalina Tuluc, Thomas Jefferson UniversityFollow
Balázs Győrffy
Jaime Caro, Thomas Jefferson UniversityFollow
Nancy J. Philp, Thomas Jefferson UniversityFollow
Ramon Bartrons
Ubaldo Martinez-Outshoorn, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

7-27-2023

Comments

This article is the author’s final published version in the International Journal of Cancer, Volume 153, Issue 9, Nov 2023, Pages 1671‐1683.

The published version is available at https://doi.org/10.1002%2Fijc.34660. Copyright © 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

Publication made possible in part by support through a transformative agreement between Thomas Jefferson University and the publisher.

Abstract

Breast cancer is composed of metabolically coupled cellular compartments with upregulation of TP53 Induced Glycolysis and Apoptosis Regulator (TIGAR) in carcinoma cells and loss of caveolin 1 (CAV1) with upregulation of monocarboxylate transporter 4 (MCT4) in fibroblasts. The mechanisms that drive metabolic coupling are poorly characterized. The effects of TIGAR on fibroblast CAV1 and MCT4 expression and breast cancer aggressiveness was studied using coculture and conditioned media systems and in-vivo. Also, the role of cytokines in promoting tumor metabolic coupling via MCT4 on cancer aggressiveness was studied. TIGAR downregulation in breast carcinoma cells reduces tumor growth. TIGAR overexpression in carcinoma cells drives MCT4 expression and NFkB activation in fibroblasts. IL6 and TGFB drive TIGAR upregulation in carcinoma cells, reduce CAV1 and increase MCT4 expression in fibroblasts. Tumor growth is abrogated in the presence of MCT4 knockout fibroblasts and environment. We discovered coregulation of c-MYC and TIGAR in carcinoma cells driven by lactate. Metabolic coupling primes the tumor microenvironment allowing for production, uptake and utilization of lactate. In sum, aggressive breast cancer is dependent on metabolic coupling.

Recommended Citation

Roche, Megan E.; Ko, Ying-Hui; Domingo-Vidal, Marina; Lin, Zhao; Whitaker-Menezes, Diana; Birbe, Ruth C.; Tuluc, Madalina; Győrffy, Balázs; Caro, Jaime; Philp, Nancy J.; Bartrons, Ramon; and Martinez-Outshoorn, Ubaldo, "TP53 Induced Glycolysis and Apoptosis Regulator and Monocarboxylate Transporter 4 Drive Metabolic Reprogramming With c-MYC and NFkB Activation in Breast Cancer" (2023). Department of Medical Oncology Faculty Papers. Paper 308.
https://jdc.jefferson.edu/medoncfp/308

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

PubMed ID

37497753

Language

English