Hypoxia Drives Breast Tumor Malignancy through a TET-TNFα-p38-MAPK Signaling Axis

Min-Zu Wu; Su-Feng Chen; Shin Nieh; Christopher Benner; Luo-Ping Ger; Chia-Ing Jan; Li Ma; Chien-Hung Chen; Tomoaki Hishida; Hong-Tai Chang; Yaoh-Shiang Lin; Nuria Montserrat; Pedro Gascon; Ignacio Sancho-Martinez; Juan Carlos Izpisua Belmonte

doi:10.1158/0008-5472.CAN-14-3208

Hypoxia Drives Breast Tumor Malignancy through a TET-TNFα-p38-MAPK Signaling Axis

Cancer Res. 2015 Sep 15;75(18):3912-24. doi: 10.1158/0008-5472.CAN-14-3208. Epub 2015 Aug 20.

Authors

Affiliations

¹ Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California.
² Department of Dental Hygiene, China Medical University, Taichung, Taiwan. Department of Pathology, National Defense Medical Centre and Tri-Service General Hospital, Taipei, Taiwan.
³ Department of Pathology, National Defense Medical Centre and Tri-Service General Hospital, Taipei, Taiwan.
⁴ Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies, La Jolla, California.
⁵ Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan. Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
⁶ Department of Pathology, China Medical University and Hospital, Taichung, Taiwan.
⁷ Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
⁸ Department of Otolaryngology-Head and Neck Surgery, National Defense Medical Centre and Tri-Service General Hospital, Taipei, Taiwan. Department of Otolaryngology-Head and Neck Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
⁹ Department of Medical Oncology, Hospital Clinic Barcelona, Barcelona University, Barcelona, Spain.
¹⁰ Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California. belmonte@salk.edu.

PMID: 26294212
DOI: 10.1158/0008-5472.CAN-14-3208

Abstract

Hypoxia is a hallmark of solid tumors that drives malignant progression by altering epigenetic controls. In breast tumors, aberrant DNA methylation is a prevalent epigenetic feature associated with increased risk of metastasis and poor prognosis. However, the mechanism by which hypoxia alters DNA methylation or other epigenetic controls that promote breast malignancy remains poorly understood. We discovered that hypoxia deregulates TET1 and TET3, the enzymes that catalyze conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), thereby leading to breast tumor-initiating cell (BTIC) properties. TET1/3 and 5hmC levels were closely associated with tumor hypoxia, tumor malignancy, and poor prognosis in breast cancer patients. Mechanistic investigations showed that hypoxia leads to genome-wide changes in DNA hydroxymethylation associated with upregulation of TNFα expression and activation of its downstream p38-MAPK effector pathway. Coordinate functions of TET1 and TET3 were also required to activate TNFα-p38-MAPK signaling as a response to hypoxia. Our results reveal how signal transduction through the TET-TNFα-p38-MAPK signaling axis is required for the acquisition of BTIC characteristics and tumorigenicity in vitro and in vivo, with potential implications for how to eradicate BTIC as a therapeutic strategy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

5-Methylcytosine / analogs & derivatives
Animals
Breast Neoplasms / genetics*
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Cell Hypoxia / genetics
Cell Hypoxia / physiology*
Cell Line, Tumor
Chromatin Immunoprecipitation
Cytosine / analogs & derivatives
Cytosine / biosynthesis
DNA Methylation*
DNA-Binding Proteins / biosynthesis
DNA-Binding Proteins / genetics
DNA-Binding Proteins / physiology*
Dioxygenases / biosynthesis
Dioxygenases / genetics
Dioxygenases / physiology*
Female
Gene Expression Regulation, Neoplastic
Heterografts
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Mice
Mice, Nude
Mixed Function Oxygenases
Molecular Sequence Data
Neoplasm Proteins / biosynthesis
Neoplasm Proteins / genetics
Neoplasm Proteins / physiology*
Neoplastic Stem Cells / cytology
Neoplastic Stem Cells / enzymology
Prognosis
Promoter Regions, Genetic / genetics
Proto-Oncogene Proteins / biosynthesis
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / physiology*
Recombinant Fusion Proteins / biosynthesis
Retrospective Studies
Signal Transduction / physiology
Tumor Necrosis Factor-alpha / biosynthesis
Tumor Necrosis Factor-alpha / genetics
Tumor Necrosis Factor-alpha / physiology*
p38 Mitogen-Activated Protein Kinases / physiology*

Substances

DNA-Binding Proteins
HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
Neoplasm Proteins
Proto-Oncogene Proteins
Recombinant Fusion Proteins
Tumor Necrosis Factor-alpha
5-hydroxymethylcytosine
5-Methylcytosine
Cytosine
Mixed Function Oxygenases
TET1 protein, human
TET3 protein, human
Dioxygenases
p38 Mitogen-Activated Protein Kinases

Associated data

GEO/GSE60434