TY - JOUR
T1 - Redox signaling by glutathione peroxidase 2 links vascular modulation to metabolic plasticity of breast cancer
AU - Ren, Zuen
AU - Liang, Huizhi
AU - Galbo, Phillip M.
AU - Dharmaratne, Malindrie
AU - Kulkarni, Ameya S.
AU - Fard, Atefeh Taherian
AU - Aoun, Marie Louise
AU - Martinez-Lopez, Nuria
AU - Suyama, Kimita
AU - Benard, Outhiriaradjou
AU - Zheng, Wei
AU - Liu, Yang
AU - Albanese, Joseph
AU - Zheng, Deyou
AU - Mar, Jessica C.
AU - Singh, Rajat
AU - Prystowsky, Michael B.
AU - Norton, Larry
AU - Hazan, Rachel B.
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Dr. Bridget Shafit-Zagardo and Dr. Juwen Dubois for expert help in immunohistochemistry; and Dr. David Reynolds at the genomic core facility, the histology core, and the Analytical Imaging Facility, the National Cancer Institute Albert Einstein Cancer Center Grant P30CA013330. We are grateful to Gene Editing and Screening (GES) Core Facility at Memorial Sloan-Kettering Cancer Center. This work was supported by grants from Breast Cancer Research Foundation, and Cure Breast Cancer Foundation to (R.B.H. and L.N.). The Breast Cancer Research Foundation was funded by generous gifts from Jane and Neil Golub. Z.R. was partly supported by a predoctoral fellowship grant from China.
Funding Information:
We thank Dr. Bridget Shafit-Zagardo and Dr. Juwen Dubois for expert help in immunohistochemistry; and Dr. David Reynolds at the genomic core facility, the histology core, and the Analytical Imaging Facility, the National Cancer Institute Albert Einstein Cancer Center Grant P30CA013330. We are grateful to Gene Editing and Screening (GES) Core Facility at Memorial Sloan-Kettering Cancer Center. This work was supported by grants from Breast Cancer Research Foundation, and Cure Breast Cancer Foundation to (R.B.H. and L.N.). The Breast Cancer Research Foundation was funded by generous gifts from Jane and Neil Golub. Z.R. was partly supported by a predoctoral fellowship grant from China.
Publisher Copyright:
© 2022 National Academy of Sciences. All rights reserved.
PY - 2022/2/22
Y1 - 2022/2/22
N2 - In search of redox mechanisms in breast cancer, we uncovered a striking role for glutathione peroxidase 2 (GPx2) in oncogenic signaling and patient survival. GPx2 loss stimulates malignant progression due to reactive oxygen species/hypoxia inducible factor-α (HIF1α)/VEGFA (vascular endothelial growth factor A) signaling, causing poor perfusion and hypoxia, which were reversed by GPx2 reexpression or HIF1α inhibition. Ingenuity Pathway Analysis revealed a link between GPx2 loss, tumor angiogenesis, metabolic modulation, and HIF1α signaling. Single-cell RNA analysis and bioenergetic profiling revealed that GPx2 loss stimulated the Warburg effect in most tumor cell subpopulations, except for one cluster, which was capable of oxidative phosphorylation and glycolysis, as confirmed by coexpression of phosphorylated-AMPK and GLUT1. These findings underscore a unique role for redox signaling by GPx2 dysregulation in breast cancer, underlying tumor heterogeneity, leading to metabolic plasticity and malignant progression.
AB - In search of redox mechanisms in breast cancer, we uncovered a striking role for glutathione peroxidase 2 (GPx2) in oncogenic signaling and patient survival. GPx2 loss stimulates malignant progression due to reactive oxygen species/hypoxia inducible factor-α (HIF1α)/VEGFA (vascular endothelial growth factor A) signaling, causing poor perfusion and hypoxia, which were reversed by GPx2 reexpression or HIF1α inhibition. Ingenuity Pathway Analysis revealed a link between GPx2 loss, tumor angiogenesis, metabolic modulation, and HIF1α signaling. Single-cell RNA analysis and bioenergetic profiling revealed that GPx2 loss stimulated the Warburg effect in most tumor cell subpopulations, except for one cluster, which was capable of oxidative phosphorylation and glycolysis, as confirmed by coexpression of phosphorylated-AMPK and GLUT1. These findings underscore a unique role for redox signaling by GPx2 dysregulation in breast cancer, underlying tumor heterogeneity, leading to metabolic plasticity and malignant progression.
KW - Breast cancer
KW - HIF1α
KW - ROS signaling
KW - glutathione peroxidase 2
KW - metabolism
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U2 - 10.1073/pnas.2107266119
DO - 10.1073/pnas.2107266119
M3 - Article
C2 - 35193955
AN - SCOPUS:85125155107
SN - 0027-8424
VL - 119
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 8
M1 - e2107266119
ER -
